CN105189520B - Carbostyril derivative - Google Patents

Carbostyril derivative Download PDF

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Publication number
CN105189520B
CN105189520B CN201480024178.8A CN201480024178A CN105189520B CN 105189520 B CN105189520 B CN 105189520B CN 201480024178 A CN201480024178 A CN 201480024178A CN 105189520 B CN105189520 B CN 105189520B
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Prior art keywords
dihydro
naphthyridines
pyridos
dihydros
amino
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CN105189520A (en
Inventor
斯特凡妮·恩德林-帕皮
克利斯汀·胡布施沃林
格奥尔格·鲁艾迪
科妮莉亚·朱姆布鲁恩
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Aidu West Pharmaceutical Co. Ltd.
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Actelion Pharmaceuticals Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Abstract

The present invention relates to formula (I) antimicrobial compoundWherein R1, U, V and A be defined as in the description；Purposes containing the medical composition of the compound and the compound in manufacture is used to treat the medicine of bacterium infection.

Description

Carbostyril derivative
Used the present invention relates to antibacterial quinolones derivative, containing the medical composition of the derivative and the compound in manufacture Purposes in the medicine for the treatment of bacterium infection.The compound is effective against the various mankind and veterinary pathogenic body (especially including leather The Lan Shi positives (Gram-positive) and Gram-negative (Gram-negative) is aerobic and anaerobic bacteria and mycobacteria (mycobacteria), and especially multi-medicament resistant gram negative bacteria) useful antimicrobial.
Widely using for antibiotic applies selective evolution pressure to microorganism, so as to produce the resistance machine based on heredity System.Modern medicine and social economy's behavior because produce situation that pathogen microorganism slowly grows in (such as) joint prosthesis and Aggravate resistance produced problem because supporting the storage of the long-term host in (such as) immunocompromised patient.
In hospital environment, the more and more staphylococcus aureus (Staphylococcus aureus) of multi-quantity, pneumonia Streptococcus (Streptococcus pneumoniae), enterococcus (Enterococcus spp.), enterobacteriaceae (Enterobacteriacea), Acinetobacter baumannii (Acinetobacter baumanii) and Pseudomonas aeruginosa The bacterial strain (main infection source) of (Pseudomonas aeruginosa) just becoming it is resistant to multi-medicament and therefore, it is difficult to If (not impossible) treatment.Gram negative organism is especially true, and wherein the situation is just becoming troubling, and this is because several Do not ratify novel agents over 10 years always and research and development channel seems vacancy.
Therefore, it is badly in need of being directed to Gram-negative tolerant bacteria, especially anti-third generation cephalosporin in medical industry (cephalosporins) and carbapenem (carbapenem) Klebsiella pneumoniae (Klebsiella Pneumonia) and multi-medicament resistance Pseudomonas aeruginosa and Acinetobacter baumannii novel anti-bacterial compounds.
WO2004/087145, WO2006/081289, WO2008/006648, WO 2010/045987 and WO2010/ 084152 elaborates antimicrobial compound, and it includes and is connected to quinoline, quinoline-2-one and its azepine isostere via interval base (azaisostere) two ring pyridine fragments
Some open files be related to 7- fluoquinolones or 7- fluorine naphthyridones fragments compound (for example, see： International Journal of Antimicrobial Agents 2010,35(4),405-409；Bioorganic& Medicinal Chemistry 2008,16(4),1784-1795；Bioorganic&Medicinal Chemistry Letters 2012,22(7),2428-2433；Bioorganic&Medicinal Chemistry Letters 2012,22 (18),5971-5975；WO 2011/094260；WO 2011/034971；WO 2010/025906；WO 2010/019208；WO 2009/064792；US 8,222,407；US 6,777,420；WO 2002/102792；WO 1996/004286；WO2013/ 029548；WO2013/142628).
WO2013/068948 discloses the antimicrobial compound of Bao Han oxazole pyridines part.
The present invention provides combination quinolone or naphthyridones primitive (motif) and the novel anti-bacterial chemical combination of the two rings pyridine fragment Thing.
1) first embodiment of the present invention system is on compound of formula I
Wherein
R1Represent (C1-C3) alkyl (especially methyl or ethyl), or R1Represent (C3-C5) cycloalkyl (especially cyclopropyl) (its In in the first sub- embodiment, R1Represent methyl or ethyl, especially methyl；And in the second sub- embodiment, R1Represent cyclopropyl)；
U represents CH or N；
V represents O or S (especially S)；And
A is represented and is attached to or inserted with six selected from hexamethylene -1,4- diyls, piperidines -1,4- diyls and piperazine -1,4- diyls The linking group being made up of unitary, binary or ternary saturated straight chain group of cyclic group；Wherein the linking group (is included The group of both straight chain group and six-membered cyclic group) containing two or three nitrogen-atoms altogether, the wherein grade nitrogen-atoms passes through At least two carbon atoms are separated from each other.
2) second embodiment is related to according to embodiment 1) described in compound of formula I；Wherein
R1Represent methyl or ethyl；Or R1Represent cyclopropyl
(especially R1Represent methyl or cyclopropyl)
(wherein in the first sub- embodiment 2a), R1Represent methyl；And
In the second sub- embodiment 2b), R1Represent cyclopropyl)；
U represents CH or N；
V represents O or S (especially S)；And
A represents the group selected from following group：
Wherein
D represents key or CH2；And
E represents key, CH2Or CH2CH2；
(wherein, in sub- embodiment, A is especially selected from group A1And/or A4)。
In this patent application, the key described with dotted line shows the attachment point of described group.In two attachment points Under situation, molecule or group should be read from left to right.For example, the group A hereafter described2
Mean divalence 4- (2- amino-ethyls)-piperidin-1-yl, wherein the left-end point nitrogen-atoms with a hydrogen atom is Naphthyridones/quinolone ring of compound of formula I is attached to, and the nitrogen-atoms of piperidine ring is attached to CH2Group is so as to be connected to Formulas I 3- oxo -3,4- dihydro -2H- pyridos [3,2-b] [the 1,4] oxazines -6- bases/3- oxo -3,4- dihydro -2H- pyrroles of compound Pyridine simultaneously [3,2-b] [1,4] thiazine -6- base sections.
To avoid any query, hexamethylene-base section of Isosorbide-5-Nitrae-two is for group A1When：
It is defined as the relatively-stationary configuration with trans [or (1r, 4r)].
Various embodiments of the present invention are presented below：
3) another embodiment is related to according to embodiment 1) or compound of formula I 2), wherein V represents S.
4) another embodiment is related to according to embodiment 1) or compound of formula I 2), wherein V represents O.
5) another embodiment is related to according to embodiment 1) any one of 4) to compound of formula I, wherein U represents N.
6) another embodiment is related to according to embodiment 1) any one of 4) to compound of formula I, wherein U represents CH.
7) another embodiment is related to according to embodiment 1) any one of 6) to compound of formula I, wherein A is represented selected from following Group in group：
(wherein, in sub- embodiment, A is especially selected from group A1And/or A4；Especially A is A1-2Or A4-3)。
8) another embodiment is related to according to embodiment 1) any one of 6) to compound of formula I, wherein A is represented selected from following Group in group：
(especially A represents group A1-2)。
9) another embodiment is related to according to embodiment 1) any one of 6) to compound of formula I, wherein A is represented selected from following Group in group：
10) another embodiment is related to according to embodiment 1) any one of 6) to compound of formula I, wherein A represent be selected from Group in lower group：
11) another embodiment is related to according to embodiment 1) any one of 6) to compound of formula I, wherein A is represented：
12) another embodiment is related to according to embodiment 1) any one of 6) to compound of formula I, wherein A represent be selected from Group in lower group：
(especially A represents group A4-3)。
13) another embodiment is related to according to embodiment 1) any one of 6) to compound of formula I, wherein A is represented：
14) according to embodiment 1) specific compound of formula I be selected from the group that consists of：
Anti-form-1-cyclopropyl-6- fluorin-4-oxygens generation-7- (4- [(3- oxo-3,4- dihydro-2H- pyridos [3,2-b] [1, 4] thiazine -6- ylmethyls)-amino]-methyl }-Cyclohexylamino) -1,4- dihydros-[1,8] naphthyridines -3- formic acid；
Anti-form-1-cyclopropyl-6- fluorin-4-oxygens generation-7- 4- [(3- oxo-3,4- dihydro-2H- pyridos [3,2-b] [1, 4] thiazine -6- ylmethyls)-amino]-Cyclohexylamino } -1,4- dihydros-[1,8] naphthyridines -3- formic acid；
1- cyclopropyl -6- fluorin-4-oxygens generation -7- (2- { 4- [(3- oxo -3,4- dihydro -2H- pyridos [3,2-b] [1,4] Thiazine -6- ylmethyls)-amino]-piperidin-1-yl }-ethyl) -1,4- dihydros-[1,8] naphthyridines -3- formic acid；
1- cyclopropyl -6- fluorin-4-oxygens generation -7- (4- { 2- [(3- oxo -3,4- dihydro -2H- pyridos [3,2-b] [1,4] Thiazine -6- ylmethyls)-amino]-ethyl }-piperazine -1- bases) -1,4- dihydros-[1,8] naphthyridines -3- formic acid；
1- cyclopropyl -6- fluorin-4-oxygens generation -7- (4- { 2- [(3- oxo -3,4- dihydro -2H- pyridos [3,2-b] [1,4] Thiazine -6- ylmethyls)-amino]-ethyl }-piperidin-1-yl) -1,4- dihydros-[1,8] naphthyridines -3- formic acid；
1- cyclopropyl -6- fluorin-4-oxygens generation -7- { 2- [1- (3- oxos -3,4- dihydro -2H- pyridos [3,2-b] [1,4] thiophenes Piperazine -6- ylmethyls)-piperidin-4-yl]-ethylamino } -1,4- dihydros-[1,8] naphthyridines -3- formic acid；
1- cyclopropyl -6- fluorin-4-oxygens generation -7- (4- { [(3- oxos -3,4- dihydro -2H- pyridos [3,2-b] [1,4] thiophenes Piperazine -6- ylmethyls)-amino]-methyl }-piperidin-1-yl) -1,4- dihydros-[1,8] naphthyridines -3- formic acid；
Anti-form-1-cyclopropyl-6- fluorin-4-oxygens generation-7- (4- [(3- oxo-3,4- dihydro-2H- pyridos [3,2-b] [1, 4] oxazine -6- ylmethyls)-amino]-methyl }-Cyclohexylamino) -1,4- dihydros-[1,8] naphthyridines -3- formic acid；
1- cyclopropyl -6- fluorin-4-oxygens generation -7- (4- { [(3- oxos -3,4- dihydro -2H- pyridos [3,2-b] [1,4] thiophenes Piperazine -6- ylmethyls)-amino]-methyl }-piperidin-1-yl methyl) -1,4- dihydros-[1,8] naphthyridines -3- formic acid；
1- cyclopropyl -6- fluorin-4-oxygens generation -7- { 4- [(3- oxos -3,4- dihydro -2H- pyridos [3,2-b] [1,4] thiophenes Piperazine -6- ylmethyls)-amino]-piperidin-1-yl } -1,4- dihydros-[1,8] naphthyridines -3- formic acid；And
1- cyclopropyl -6- fluorin-4-oxygens generation -7- (4- { 2- [(3- oxo -3,4- dihydro -2H- pyridos [3,2-b] [1,4] Thiazine -6- ylmethyls)-amino]-ethyl }-piperazine -1- bases) -1,4- dihydro-quinoline -3- formic acid.
15) according to embodiment 1) other specific compound of formula I be selected from the group that consists of：
1- cyclopropyl -6- fluorin-4-oxygens generation -7- (4- { 2- [(3- oxo -3,4- dihydro -2H- pyridos [3,2-b] [1,4] Oxazine -6- ylmethyls)-amino]-ethyl }-piperazine -1- bases) -1,4- dihydros-[1,8] naphthyridines -3- formic acid；
The trans fluoro- 1- methyl -4- oxos -7- of -6- (4- { [(3- oxo -3,4- dihydro -2H- pyridos [3,2-b] [1,4] Thiazine -6- ylmethyls)-amino]-methyl }-Cyclohexylamino) -1,4- dihydros-[1,8] naphthyridines -3- formic acid；
The trans fluoro- 1- methyl -4- oxos -7- of -6- (4- { [(3- oxo -3,4- dihydro -2H- pyridos [3,2-b] [1,4] Oxazine -6- ylmethyls)-amino]-methyl }-Cyclohexylamino) -1,4- dihydros-[1,8] naphthyridines -3- formic acid；
Anti-form-1-ethyl-6- fluorin-4-oxygens generation-7- (4- { [(3- oxo-3,4- dihydro-2H- pyridos [3,2-b] [1,4] Thiazine -6- ylmethyls)-amino]-methyl }-Cyclohexylamino) -1,4- dihydros-[1,8] naphthyridines -3- formic acid；
The fluoro- 1- methyl -4- oxos -7- of 6- (4- { 2- [(3- oxo -3,4- dihydro -2H- pyridos [3,2-b] [1,4] Evil Piperazine -6- ylmethyls)-amino]-ethyl }-piperidin-1-yl) -1,4- dihydros-[1,8] naphthyridines -3- formic acid；And
The fluoro- 1- methyl -4- oxos -7- of 6- (4- { 2- [(3- oxos -3,4- dihydro -2H- pyridos [3,2-b] [1,4] thiophenes Piperazine -6- ylmethyls)-amino]-ethyl }-piperidin-1-yl) -1,4- dihydros-[1,8] naphthyridines -3- formic acid.
16) therefore, the present invention relates to such as embodiment 1) defined in compound of formula I, or closed in view of its corresponding relies on It is further by embodiment 2) any one of 15) compound that is limited to feature；Its pharmaceutically acceptable salt；And the change Compound is as the purposes of medicine, and it is particularly for preventing or treating bacterium infection as noted in the discussion, particularly for prevention Or treat by gramnegative bacterium (especially such as Acinetobacter baumannii, bulkholderia cepasea (Burkholderia) (example Such as, Burkholderia (Burkholderia cepacia)), citric acid bacillus (Citrobacter spp.), production Gas enterobacteria (Enterobacter aerogenes), enterobacter cloacae (Enterobacter cloacae), Escherichia coli The sour klebsiella (Klebsiella oxytoca) of (Escherichia coli), production, Klebsiella pneumoniae, clayey Serratieae (Serratia marcescens), germ oligotrophy unit cell (Stenotrophomonas maltophilia) And Pseudomonas aeruginosa) caused by bacterium infection：Such as urinary tract infections；Systemic infection (bacteremia and septicemia)；Surgical infection；Abdomen Interior infection and Lung infection (including with Lung infection in Cystic fibrotic patient).Therefore, especially following and formula (I) is changed The related embodiment of compound is possible and is intended in individualized form and is specifically disclosed in this in individualized form：
1、2、3+1、3+2、4+1、4+2、5+1、5+2、5+3+1、5+3+2、5+4+1、5+4+2、6+1、6+2、6+3+1、6+3 +2、6+4+1、6+4+2、7+1、7+2、7+3+1、7+3+2、7+4+1、7+4+2、7+5+1、7+5+2、7+5+3+1、7+5+3+2、7+ 5+4+1、7+5+4+2、7+6+1、7+6+2、7+6+3+1、7+6+3+2、7+6+4+1、7+6+4+2、8+1、8+2、8+3+1、8+3+ 2、8+4+1、8+4+2、8+5+1、8+5+2、8+5+3+1、8+5+3+2、8+5+4+1、8+5+4+2、8+6+1、8+6+2、8+6+3+ 1、8+6+3+2、8+6+4+1、8+6+4+2、9+1、9+2、9+3+1、9+3+2、9+4+1、9+4+2、9+5+1、9+5+2、9+5+3+ 1、9+5+3+2、9+5+4+1、9+5+4+2、9+6+1、9+6+2、9+6+3+1、9+6+3+2、9+6+4+1、9+6+4+2、10+1、10 +2、10+3+1、10+3+2、10+4+1、10+4+2、10+5+1、10+5+2、10+5+3+1、10+5+3+2、10+5+4+1、10+5+ 4+2、10+6+1、10+6+2、10+6+3+1、10+6+3+2、10+6+4+1、10+6+4+2、11+1、11+2、11+3+1、11+3+ 2、11+4+1、11+4+2、11+5+1、11+5+2、11+5+3+1、11+5+3+2、11+5+4+1、11+5+4+2、11+6+1、11+6 +2、11+6+3+1、11+6+3+2、11+6+4+1、11+6+4+2、12+1、12+2、12+3+1、12+3+2、12+4+1、12+4+2、 12+5+1、12+5+2、12+5+3+1、12+5+3+2、12+5+4+1、12+5+4+2、12+6+1、12+6+2、12+6+3+1、12+6 +3+2、12+6+4+1、12+6+4+2、13+1、13+2、13+3+1、13+3+2、13+4+1、13+4+2、13+5+1、13+5+2、13 +5+3+1、13+5+3+2、13+5+4+1、13+5+4+2、13+6+1、13+6+2、13+6+3+1、13+6+3+2、13+6+4+1、13 +6+4+2。
In list above, numeral refers to the embodiment according to embodiment numbering presented above, and "+" is indicated to another The dependence of one embodiment.Different individualized embodiments are separated by pause mark.In other words, for example, " 8+3+1 " refers to dependent on implementation Example 3) and dependent on embodiment 1) embodiment 8), i.e., embodiment " 8+3+1 " corresponds to further by embodiment 3) and spy 8) Levy the embodiment 1 of limitation) compound.
Unless the definition being expressly recited in addition provides wider or narrower definition, otherwise definition provided in this article is intended to one Ground is caused to be applied to such as embodiment 1) any one of 16) and (having made necessary amendment) entire disclosure and claim institute to Formula (I) compound of definition.It should be fully understood by, the definition of term or preferred definition are as herein defined independently of (and combination) Any definition of any or every other term or preferred definition are defined and replaceable corresponding term.
Term " alkyl " refers to saturated straight chain or tool branched hydrocarbyl containing 1 to 4 carbon atom when being used alone or in combination.Art Language " (C1-Cx) alkyl " (x is integer) refer to the alkyl containing 1 to x carbon atom.For example, (C1-C4) alkyl contains 1 to 4 carbon Atom.The representative example of alkyl includes methyl, ethyl, propyl group, isopropyl, normal-butyl, isobutyl group, sec-butyl and the tert-butyl group. It is preferred that methyl and ethyl.Most preferable.For substituent R1, term (C1-C3) alkyl especially means methyl or ethyl；It is preferred that Methyl.
Term " cycloalkyl " refers to the saturated cyclic hydrocarbyl group containing 3 to 7 carbon atoms when being used alone or in combination.Term “(C3-Cx) cycloalkyl " (x is integer) refer to the cycloalkyl containing 3 to x carbon atom.For example, (C3-C5) cycloalkyl contain 3 to 5 carbon atoms.The representative example of cycloalkyl includes cyclopropyl, cyclobutyl and cyclopenta.For substituent R1, term (C3-C5) Cycloalkyl preferably means cyclopropyl.
The term " quinolone resistant " or " methicillin resistance (methicillin- related to bacterium bacterial strain Resistant) " it is related to bacterium bacterial strain, Ciprofloxacin (ciprofloxacin) or methicillin as used herein Correspondingly resisting the MIC of the bacterium bacterial strain, (MIC is using being set forth in " Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically ", Recognized Standards, the 7th edition, Clinical and Laboratory Standards Institute (CLSI) Standard method in Document M7-A7, Wayne, PA, USA, 2006 is measured) it is at least 16mg/l.It is related to bacterium bacterial strain Term " multi-drug resistance " refer to the bacterium bacterial strain resistant to three class above antibiotic as used herein.
If suitably and conveniently, to any salt for being all interpreted as also referring to this compound, especially of referring to of compound of formula I Pharmaceutically acceptable salt.
Term " pharmaceutically acceptable salt " refers to keep the expectation bioactivity of target compound and shows minimum not Expect the salt of toxicology effect.Such salt is according to the presence of target compound neutral and alkali and/or acidic-group including inorganic Or organic acid and/or base addition salts.For bibliography, for example, see " Handbook of Pharmaceutical Salts.Properties, Selection and Use. ", P.Heinrich Stahl, Camille G.Wermuth (are compiled Volume), Wiley-VCH, 2008；And " Pharmaceutical Salts and Co-crystals ", Johan Wouters and Luc Qu é r é (editor), RSC Publishing, 2012.
Used unless be related to temperature, the term " about " being otherwise placed in before numerical value " X " refers to from X-10%X in this application X+10%X interval is extended to, and preferably refers to extend to X+5%X interval from X-5%X.In the specific situation of temperature Under, the term " about " being placed in before temperature Y refers to extend in this application Y+10 DEG C of interval from Y-10 DEG C of temperature, and preferably Ground refers to extend to Y+5 DEG C of interval from Y-5 DEG C.As used herein, term " room temperature " refers to about 25 DEG C of temperature.
Whenever using word " between ... between " illustrate number range when, it should be understood that the end points of indicated scope is clearly wrapped Include in this range.For example：If illustrating temperature range between 40 DEG C and 80 DEG C, this means that 40 DEG C and 80 DEG C of end points includes In this range；If or be integer between 1 and 4 by variable-definition, this means that variable is integer 1,2,3 or 4.
The present invention also includes through isotope marks, especially passing through2H (deuterium) marks such as embodiment 1) to 16) and any one of institute The compound of formula I of definition, such compound is identical with compound of formula I, and simply one or more atoms are respectively hung oneself with identical Atomic number but atomic mass are different from the atomic substitutions of the atomic mass generally found in nature.Through isotope marks, Especially pass through2The compound of formula I and its salt of H (deuterium) marks are within the scope of the present invention.Use higher isotope2H (deuterium) substitution hydrogen may be such that Metabolic stability is improved, so that the extension of (such as) vivo half-life or dose requirements reduction, or may be such that to cell color The suppression reduction of plain P450 enzymes, so that (such as) security feature is improved.In one embodiment of this invention, compound of formula I Without isotope marks, or it is only marked through one or more D-atoms.In sub- embodiment, compound of formula I is completely without same position Element mark.Compound of formula I through isotope marks can be prepared with similar method set forth below, but use Suitable agents Or the appropriate Isotopic variations of parent material.
Such as embodiment 1) any one of 16) it can be used as doctor to compound of formula I defined in and its pharmaceutically acceptable salt Medicine, such as in the medical composition shape for enteral (such as especially oral) or parenteral administration (including local application or suction) Formula.
In a preferred embodiment of the invention, such as embodiment 1) any one of 16) to the administration of compound of formula I defined in Amount will be between 1mg/ days and 2000mg/ days, particular between 50mg/ days and 1500mg/ days, more specifically between 100mg/ It and between 1000mg/ days, particular between 250mg/ days and 1000mg/ days.
Another aspect of the present invention is medical composition, and it is included such as embodiment 1) any one of 16) to Formulas I defined in Compound or its pharmaceutically acceptable salt and pharmaceutically acceptable excipient/carrier materials.The medical composition of the present invention Containing at least one compound of formula I (or its pharmaceutically acceptable salt) as activating agent, and it can also contain other known antibiosis Element.
The generation of medical composition can well known to a person skilled in the art either type (for example, see Remington, The Science and Practice of Pharmacy, the 21st edition (2005), the 5th part, " Pharmaceutical Manufacturing " [being published by Lippincott Williams＆Wilkins]) by by the compound of formula I illustrated or its Pharmaceutically acceptable salt (combinations of substances for optionally having therapeutic value with other) together with suitable nontoxic, inertia, treat simultaneous Galenica (galenical) form of medication is made in capacitive solid or liquid carrier material and (if desired) conventional pharmaceutical adjuvants Realize.
The compound of formula I (i.e. example 1 above) of the present invention is to 16) any one of defined in compound of formula I) be suitable to use Make the chemotherapeutic activity compound in the mankind and veterinary medicine, and be suitable as being used to preserve inorganic and organic material (specifically For, all types of organic materials, such as polymer, lubricant, coating, fiber, leather, paper and timber) material.
Such as embodiment 1) any one of 16) show especially resistant against Gram negative organism to compound of formula I defined in Antibacterial activity.Its bacterium infection that can be used in treatment mammal, the especially mankind.Such compound also can be used for animal doctor In, for example, treat the infection in livestock animals and companion animals (including pig, ruminant, horse, dog, cat and poultry).
Such as embodiment 1) any one of 16) it is used especially for treating various bacterium infections to compound of formula I defined in, especially Its infection mediated by gramnegative bacterium.Such bacterium infection includes nosocomial pneumonia in patients, urinary tract infections, systemic infection (bacteremia and septicemia), skin and soft tissue infection, surgical infection, infection in abdomen, Lung infection are (including with Cystic fiber Be denatured the Lung infection in patient), endocarditis, infection in diabetic foot, osteomyelitis and central nervous system infection.In sub- embodiment In, the specific infection as caused by gramnegative bacterium is to be selected from urinary tract infections；Systemic infection (bacteremia and septicemia)；Outside Section infects；Infection and Lung infection (including with Lung infection in Cystic fibrotic patient) in abdomen；Especially selected from urine Road feel contaminates；Infection and Lung infection (including with Lung infection in Cystic fibrotic patient) in abdomen；Especially selected from urine Road feel, which contaminates, and abdomen is interior infects.
Such as embodiment 1) any one of 16) it can be used for treating or preventing by Fermented or non-to compound of formula I defined in The bacterium infection of Fermented gramnegative bacterium mediation (especially listed above shows bacterium sense by what gramnegative bacterium mediated Dye), the bacterium infection especially as caused by neurological susceptibility and multi-medicament resistance (MDR) gramnegative bacterium.Such gram The example of negative bacteria includes acinetobacter calcoaceticus (such as Acinetobacter baumannii or hemolytic acinetobacter calcoaceticus (Acinetobacter Haemolyticus)), actinobacillus actinomycetem comitans (Actinobacillus actinomycetemcomitans), achromobacter (Achromobacter spp.) (such as Achromobacter xylosoxidans (Achromobacter xylosoxidans)) or excrement without Color bacillus (Achromobacter faecalis)), Aerononas punctata (Aeromonas spp.) (such as thermophilic aquatic products Aeromonas (Aeromonas hydrophila)), bacteroid (Bacteroides spp.) (such as bacteroides fragilis (Bacteroides Fragilis), bacteroides thetaiotaomicron (Bacteroides thetaiotaomicron), bacteroides disiens (Bacteroides Distasonis), bacteroides ovatus (Bacteroides ovatus) or bacteroides vulgatus (Bacteroides Vulgatus)), Han Se strangles Ba Dongshi bacillus (Bartonella hensenae), Bo Deshi bacillus (Bordetella spp.) (such as pertussis Bo Deshi bacillus (Bordetella pertussis)), Borrelia (Borrelia spp.) (such as primary Borrelia burgdorferi (Borrelia Burgdorferi)), Brucella (Brucella spp.) (such as Mediterranean fruit fly Bu Shi bars Bacterium (Brucella melitensis)), bulkholderia cepasea (such as Burkholderia (Burkholderia Cepacia), Burkholderia pseudomallei (Burkholderia pseudomallei) or Burkholderia mallei (Burkholderia mallei)), curved bar bacterium (Campylobacter spp.) (such as jejunum curved bar bacterium (Campylobacter jejuni), fetus curved bar bacterium (Campylobacter fetus) or large intestine curved bar bacterium (Campylobacter coli)), western western bacterium (Cedecea), Chlamydia (Chlamydia spp.) (such as pneumonia coating Bacterium, trachoma Chlamydia), citric acid bacillus (such as difference citric acid bacillus (Citrobacter diversus) (kirschner (koseri)) or citrobacter freundii (Citrobacter freundii)), Pu Nai Shi Corks steadite (Coxiella Burnetii), tarda (Edwardsiella spp.) (such as Edwardsiella tarda (Edwardsiella Tarda)), Cha Feiailixi bodies (Ehrlichia chafeensis), erode Aitken bacterium (Eikenella corrodens), intestines Bacillus (Enterobacter spp.) (such as enterobacter cloacae, clostridium perfringen, gathers enterobacteria (Enterobacter Agglomerans), Escherichia coli), soil draw Wen bacillus (Francisella tularensis), thin clostridium (Fusobacterium spp.), haemophilus (Haemophilus spp.) (such as Hemophilus influenzae (acyl in β Amine enzyme positive and feminine gender) or haemophilus ducreyi (Haemophilus ducreyi)), helicobacter pylori (Helicobacter pylori), Jin Shi Kingellas (Kingella kingae), klebsiella (for example produce sour Cray primary Family name bacillus, Klebsiella pneumoniae (including coding extended spectrum β lactamases (hereafter " ESBL "), KPC, CTX-M, metal-β Lactamase and AmpC type beta lactamase persons, such beta lactamase is to currently available cynnematin, cephamycin (cephamycin), the combination of carbapenem, beta-lactam and beta-lactam/beta lactamase restrainer is resistant), nose scleroma gram Thunder Bai Shi bacillus (Klebsiella rhinoscleromatis) or ozena klebsiella (Klebsiella Ozaenae)), the thermophilic tuberculosis bacterium of veteran (Legionella pneumophila), Mannheimia haemolytica (Mannheimia Haemolyticus), moraxelle catarrhalis (Moraxella catarrhalis) (beta-lactam enzyme positive and feminine gender), Mo Shi rub root Bacterium (Morganella morganii), Neisseria (Neisseria spp.) (such as NEISSERIA GONORRHOEAE (Neisseria Gonorrhoeae) or Neisseria meningitidis (Neisseria meningitidis)), Pasteurella (Pasteurella Spp.) (such as pasteurella multocida (Pasteurella multocida)), Plesiomonas shigelloides (Plesiomonas Shigelloides), pyrroles's monad (Porphyromonas spp.) (does not understand sugared pyrroles's monad for example (Porphyromonas asaccharolytica)), Prey irrigate bacterium (Prevotella spp.) (for example human body Prey irrigate bacterium (Prevotella corporis), middle Prey irrigate bacterium (Prevotella intermedia) or dental pulp Prey irrigates bacterium (Prevotella endodontalis)), proteus (Proteus spp.) (such as Proteus rettgeri (Proteus mirabilis), proteus vulgaris (Proteus vulgaris), P.penneri (Proteus Penneri) or the glutinous proteus (Proteus myxofaciens) of production), do not understand sugared pyrroles's monad, Plesiomonas shigelloides, Providence (Providencia spp.) (such as providencia stuartii (Providencia stuartii), thunder Family name's Providence (Providencia rettgeri) or production alkali Providence (Providencia Alcalifaciens)), pseudomonad (Pseudomonas spp.) (such as Pseudomonas aeruginosa or Pseudomonas fluorescens (Pseudomonas fluorescens)), Rickettsia prowazeki (Ricketsia prowazekii), Salmonella (Salmonella spp.) (such as salmonella typhi (Salmonella typhi) or paratyphoid Salmonella (Salmonella paratyphi)), Serratia marcesens, bacillus dysenteriae (Shigella spp.) (such as Shigella flexneri (Shigella flexneri), Boydii bacillus dysenteriae (Shigella boydii), sonnei bacillus dysenteriae (Shigella Sonnei) or dysentery bacillus dysenteriae (Shigella dysenteriae)), Streptobacillus moniliformis (Streptobacillus Moniliformis), germ oligotrophy unit cell, treponema (Treponema spp.), vibrios (Vibrio spp.) (example Such as comma bacillus (Vibrio cholerae), vibrio parahaemolytious (Vibrio parahaemolyticus), Vibrio vulnificus (Vibrio vulnificus), vibrio alginolyticus (Vibrio alginolyticus)), Ye Shi bacillus (Yersinia spp.) (such as small intestine colitis Ye Shi bacillus (Yersinia enterocolitica), plague Ye Shi bacillus (Yersinia Pestis), false tuberculosis Ye Shi bacillus (Yersinia pseudotuberculosis)).
In a preferred embodiment, the example of such gramnegative bacterium is to be selected from Acinetobacter baumannii, primary gram of Hall Moral Salmonella (for example, Burkholderia), citric acid bacillus, clostridium perfringen, enterobacter cloacae, Escherichia coli, production Sour klebsiella, Klebsiella pneumoniae, Serratia marcesens, germ oligotrophy unit cell and Pseudomonas aeruginosa.In son In embodiment, such gramnegative bacterium is especially selected from citric acid bacillus, clostridium perfringen, enterobacter cloacae, large intestine Bacillus, the sour klebsiella of production, Klebsiella pneumoniae, Serratia marcesens, germ oligotrophy unit cell and Boydii are not Lever bacterium.In another sub- embodiment, specific gramnegative bacterium is Acinetobacter baumannii and especially citric acid pneumonia Bacillus.
The infection of previous lists and pathogen are interpreted as only as example and never restrictive.
Other bacterium infections that can be treated or prevented according to the inventive method and the illness related to infection referring to J.P.Sanford et al., " The Sanford Guide to Antimicrobial Therapy, " the 26th edition, (Antimicrobial Therapy companies, 1996).
Compound of formula I can program set forth below used according to the invention manufacture.
The preparation of compound of formula I
Abbreviation：
Following abbreviation is used in entire disclosure and example：
Ac acetyl group
AcOH acetic acid
Alloc allyloxy carbonyls
Aq. it is aqueous
Boc tert-butoxycarbonyls
BuLi n-BuLis
Cbz benzyloxycarbonyls
Col-umn chromatography on CC silica gel
Cipro Ciprofloxacins
Cy cyclohexyl
DAD Diode Array Detectors
Dba dibenzalacetones
DCE 1,2- dichloroethanes
DCM dichloromethane
DIPEA N, N- diisopropylethylamine
DMAP 4-dimethylaminopyridines
DMF N,N-dimethylformamides
DMSO dimethyl sulfoxides
EA ethyl acetate
ELSD EISDs
ESI electro-spray ionizations
Et ethyls
EtOH ethanol
Hept heptane
Hex hexanes
HexLi hexyllithiums
HPLC high performance liquid chroma- tographies
HV high vacuum conditions
LC liquid chromatographies
Me methyl
MeCN acetonitriles
MeOH methanol
MS mass spectrums
NMO N-methylmorpholine N- oxides
NMP N- methyl 2- Pyrrolizidine ketone
Org. it is organic
PEPPSITM- IPr [double (2,6- diisopropyl phenyls) imidazoles -2- subunits of 1,3-] (3- chloropyridines base) two Palladium bichloride (II)
Ph phenyl
The phenyl -1 of Q-Phos 1,2,3,4,5- five '-(di-t-butyl phosphino-) ferrocene
Rt room temperatures
Sat. saturation
The norcamphanyl phosphine complex compound of SK-CC01-A 2'- (dimethylamino) -2- xenyls-palladium bichloride (II) two
S-Phos 2- dicyclohexyls phosphino- -2 ', 6 '-dimethoxy-biphenyl
The tBu tert-butyl groups
TEA triethylamines
TFA trifluoroacetic acids
THF tetrahydrofurans
TLC thin-layer chromatographies
tRRetention time
UV ultraviolets
General reactions technology：
General reactions technology 1 (hydrolysis in ester to carboxylic acid)：
When ester side chain is straight chained alkyl, generally by mixed in the dioxane of water-or water-THF between 0 DEG C and 80 DEG C Implement hydrolysis using alkali metal hydroxide (such as LiOH, KOH or NaOH) processing in compound.When ester side chain is the tert-butyl group, Also hydrolysis can be implemented in the TFA or HCl of dilution in pure TFA or in organic solvent (such as ether or THF).When ester side chain is During pi-allyl, between 0 DEG C and 50 DEG C in solvent (such as THF) in the presence of tetrakis triphenylphosphine palladium (0) in allyl Implement reaction in the presence of base cation removal agent (such as morpholine, dimetone or tri-butyl tin hydride).When ester side chain is benzyl, Implement reaction in the presence of noble metal catalyst (such as Pd/C) in solvent (such as MeOH, THF or EA) under hydrogen.Introduce it Other strategies of his acid protecting group and the conventional method of the such blocking group of removal have been set forth in Protecting Groups In Organic Synthesis, the 3rd edition；1999,369-441；T.W.Greene,P.G.M.Wuts；(Publisher:John Wiley and Sons companies, New York, N.Y.) in.
General reactions technology 2 (reduction amination)：
Reaction between amine and aldehydes or ketones is being allowed via physically or chemically mode (for example, solvent distillation-water azeotropic mixture Or there is drier (such as molecular sieve, MgSO4Or Na2SO4)) remove progress in the solvent system for forming water.The solvent is usual For toluene, Hex, THF, DCM or DCE or solvent mixture (such as DCE/MeOH).It can be urged by acid traces (usual AcOH) Change the reaction.With Suitable reducing agents (such as NaBH4、NaBH3CN or NaBH (OAc)3) or via through noble metal catalyst (for example Pd/C) hydrogenate to reduce intermediate imine.The reaction be between -10 DEG C and 110 DEG C, be preferably ranges between 0 DEG C and 60 DEG C Between implement.The reaction can also a cooking-pot type method implement.It also can be molten in proton in the presence of picolin-borane complexes Implement (Sato et al., Tetrahedron (2004), 60,7899-7906) in agent (such as MeOH or water).
General reactions technology 3 (the chloro- naphthyridines -4- ketone of 7- and the chloro- quinolone substitutions of 7-)：
Make amine derivative with the fluoro- 1,4- dihydros -4- oxos -1,8- naphthyridines -3- formic acid of the chloro- 1- cyclopropyl -6- of 7- between 0 DEG C and 120 DEG C between it is anti-in the presence of organic base (such as DIPEA or TEA) in solvent (such as THF, DMF, MeCN or NMP) 3h is answered to 24h.
Make amine derivative with the chloro- 1- cyclopropyl -6- fluorin-4-oxygens of 7- for reaction or another choosing as described above of quinoline -3- formic acid It is selected as being that its alkyl, benzyl, pi-allyl or borate (for example make carboxylic acid be converted to COOB by quinolone temporal activation (OAc)2).Using borate specific situation in, after the reaction with inorganic acid (such as HCl) aqueous solution handle, it is laggard Row purifying；In addition, deprotecting ester using General reactions technology 1.Other details can be found in Comprehensive Organic Transformations.A guide to Functional Group Preparations；Second edition, R.C.Larock, Wiley-VC；New York,Chichester,Weinheim,Brisbane,Singapore,Toronto,1999.Section Amines pages 779.
General reactions technology 4 (Suzuki is coupled (Suzuki coupling))：
Making aromatic halide (usual bromide) and required boronic acid derivatives or its borate equivalent, (for example where is frequency Alcohol ester) between 20 DEG C and 120 DEG C in solvent (such as toluene, THF, dioxanes, DME or DMF) generally in water (20% To in the presence of 50%) in palladium catalyst and alkali (such as K2CO3、Cs2CO3、K3PO4, tBuONa or tBuOK) in the presence of react.Allusion quotation The example of type palladium catalyst is triaryl phosphine palladium compound, such as Pd (PPh3)4.Such catalyst also can be from common palladium source (example Such as Pd (OAc)2Or Pd2(dba)3) and part (such as trialkyl phosphine (such as PCy3Or P (tBu)3), dialkyl group phosphinobiphenyl (example Such as S-Phos) or ferrocenyl phosphine (such as Q-Phos)) in situ obtained.Another selection is that can be used and be based on palladium ring (such as SK- ) or N- heterocyclic carbenes compound (such as PEPPSI CC01-ATM- IPr) commercially available pre-catalyst.Also can be by using corresponding aromatics Triflate implements the reaction.Other versions of the reaction are to be set forth in Chem.Rev. (1995), 95,2457- 2483, Synthesis (2004), 2419-2440, Aldrichimica acta (2006), 39,17-24 and 97-111, (2008), Acc.Chem.Res. in 41,1555-1564 and references cited therein.
General reactions technology 5 (amine deprotection)：
By through noble metal catalyst (such as Pd/C or Pd (OH)2/ C) hydrogenolysis removes Cbz blocking groups.In acid bar Under part (for example, be stored in the HCl in organic solvent (such as MeOH Huo dioxanes), or pure TFA or in such as DCM equal solvents The TFA of dilution) remove Boc groups.Between 0 DEG C and 50 DEG C, in solvent (such as THF), in tetrakis triphenylphosphine palladium (0) in the presence of, Alloc is removed in the presence of allyl cation scavenger (such as morpholine, dimetone or tri-butyl tin hydride) Group.Other conventional methods for removing amine protecting group group have been set forth in Protecting Groups in Organic Synthesis, the 3rd edition (1999), 494-653；T.W.Greene,P.G.M.Wuts；(publisher：John Wiley and Sons companies, New York, N.Y.) in.
General reactions technology 6 (azide turns into amine)：
In such as MeOH or EA equal solvents azide is hydrogenated through noble metal catalyst (such as Pd/C).Another selection Can to be illustrated in 36,2558-68 and use PPh in the presence of water such as J.Med.Chem. (1993)3Implement reduction.
It is typically prepared method：
The preparation of compound of formula I：
Can by method described below, Formulas I chemical combination is manufactured by the method that is provided in example or by similar approach Thing.Optimum reaction condition can change with used specific reactant or solvent, but such condition can be by art technology Personnel are determined by routine optimisation procedures.
Hereafter chapters and sections illustrate the conventional method for preparing compound of formula I.If not indicating in addition, general group R1, U, V and A (including (such as) A1、A2、A3、A4、A5、A6, D and E) be as defined for Formulas I.Corresponding to group A1、A3、A4、A5And/or A6 Group-G-NH- mean group G represent such as the group A of the right end-NH- groups of define but lack1、A3、A4、A5And/or A6。 Equally, corresponding to formula A1And/or A2Group group-NH-Y- mean group Y represent as define but lack left-end point-NH- The group A of group1Or A2。
The general synthetic method hereafter reused in the whole text be referring to entitled " General reactions technology " chapters and sections above and It is to be set forth in wherein.In some cases, some general groups may be not simultaneous with the assembling that is illustrated in following programs and scheme Hold, and therefore will need to use blocking group.The use of blocking group is known in the industry (for example, see " Protective Groups in Organic Synthesis”,T.W.Greene,P.G.M.Wuts,Wiley-Interscience,1999)。
Compound of formula I can be obtained by following：
A) compound of structure II is deprotected using General reactions technology 1
Wherein R represents alkyl, pi-allyl or benzyl.
B) structure III compound is deprotected using General reactions technology 5
Wherein-G-N (PG)-correspond to group A (such as A6) (it is in this case, to deposit through the group PG nitrogen-atoms protected It is A6- CH2CH2Terminal nitrogen atom in NH- groups) and PG represents amine protecting group group (such as Boc, Alloc or Cbz).
C) structure I Va compounds are made using General reactions technology 2
Wherein-G-NH- corresponds to group A1、A3、A4、A5Or A6, or structure I Vb compounds
Reacted with structure V compounds
D) structure VI compounds are made using General reactions technology 3
Wherein X represents halogen (such as fluorine, chlorine or bromine), with structure VIIa compounds
Wherein group-NH-Y- corresponds to group A1Or A2, or with structure VIIb compounds react
Wherein group A represents group A4Or A6。
E) structure VIII compounds are made using General reactions technology 2
Reacted with structure VIIa compounds.
The preparation of synthetic intermediate：
Compound of structure II：
Compound of structure II can be obtained by following：
Aa) structure I Xa compounds are made using General reactions technology 2
Wherein-G-NH- corresponds to group A1、A3、A4、A5Or A6, and R represents alkyl, pi-allyl or benzyl, or structure I Xb Compound
Reacted with structure V compounds.
Bb) structure X compounds are made using General reactions technology 3
Wherein X represents halogen (such as bromine or chlorine) and R represents alkyl, pi-allyl or benzyl and structure VIIa or VIIb change Compound reacts.
Cc structure XI compounds) are made in the presence of 1,1,3,3- TMGs
Wherein R represents alkyl, pi-allyl or benzyl and structure VIIb compounds wherein A represents A4And E represents key,
Dd) the ester functional group in structure XII compounds is deprotected using appropriate General reactions technology 1
Wherein-G-N (PG)-correspond to A (such as group A6), it is in this case to exist through the group PG nitrogen-atoms protected In-CH2CH2Terminal nitrogen atom in NH- groups), PG represents amine protecting group group (such as Boc, Alloc or Cbz) and R represents alkane Base, pi-allyl or benzyl.
The compound of structure III and XII：
Structure III and XII compound can illustrate to prepare in following article scheme 1.
Scheme 1
In scheme 1, RARepresent hydrogen, alkyl, pi-allyl or benzyl.
The compound and piperazine that structure VI or X can be made are reacted, so as to obtain the intermediate of structure I -1, can be used general anti- Technology 2 is answered the intermediate is further reacted with the compound of structure I -2.Another selection is that General reactions technology 1 can be used from knot Structure XII compounds obtain structure III compound.
Structure I Va, IVb, IXa, IXb, VIII and XI compound：
(wherein-G-NH- corresponds to A to structure I Va and IXa compound4Or A6) and structure I Vb and IXb compound can be such as Hereafter illustrate to prepare in scheme 2.
Scheme 2
In scheme 2, RARepresent hydrogen, alkyl, pi-allyl or benzyl.
General reactions technology 3 can be used to make the quinoline promise of structure I I-1, II-3 and II-4 aminoderivative and structure VI or X Ketone or naphthyridinone derivatives reaction, so as to obtain structure I Va after the optional cracking Boc blocking groups using General reactions technology 5 And (wherein-G-NH- corresponds to A to IXa corresponding derivative4Or A6) and structure I Vb and IXb compound.
(wherein-G-NH represents group A to structure I Va and IXa compound3) and structure VIII and XI compound can be as follows Illustrate to prepare in literary scheme 3.
Scheme 3
In scheme 3, RARepresent hydrogen, alkyl, pi-allyl or benzyl.
General reactions technology 4 can be used to make structure VI or X quinolone or naphthyridinone derivatives and vinyl boronic acids acid anhydride III-1 (compound with pyridine) reaction, so as to obtain structure XI derivatives, such derivative can sequentially be converted to its corresponding 1,2- Glycol homologue (the 1,2- dihydroxies being for example catalyzed via osmium) and (R of structure III -2A=alkyl, pi-allyl or benzyl) or VIII(RA=hydrogen) corresponding aldehyde (such as via NaIO4Cracking).General reactions technology 2 can be used to make the aldehyde and ammonia of structure III -2 Base formic acid tBu-N- (4- piperidino methyls) ester reacts, and then removes Boc blocking groups using General reactions technology 5, so that To structure I Va and IXa compound, wherein-G-NH- corresponds to group A3。
The compound of structure V, VI and X
Structure V compounds are prepared according to WO2002/056882.Structure VI and X compound can be bought from market or EP 187376 is can be similar to prepare.
Structure VIIa and VIIb compound：
(wherein group-HN-Y- corresponds to group A to structure VIIa compounds1Or A2) or structure VIIb compounds (wherein A generations Table A4Or A6) can illustrate to prepare in following article scheme 4.
Scheme 4
General reactions technology 2 can be used to make structure I V-1, IV-2, IV-3 and IV-4 aminoderivative and structure V aldehyde Derivative sequentially reacts, and is deprotected using General reactions technology 5, so as to obtain structure VIIa derivatives (wherein-G- NH- corresponds to group A1Or A2) or structure VIIb derivatives (wherein A represents A4Or A6)。
Intermediate for synthesizing compound III, IVa-b, IXa-b, VIIa-b, VIII, XI and XII
The compound of structure I -2 can illustrate to prepare in following article scheme 5.
Scheme 5
General reactions technology 2 can be used to make 3- aminopropanes -1,2- glycol and structure V derivatives reactions, so as to be tied Structure V-2 diol, derivatives, can make the diol, derivatives and (Boc)2O is in alkali (such as NaHCO3Or DMAP) in the presence of further Reaction.Resulting structures V-3 derivatives and NaIO can be made4Reaction, so as to obtain the derivative of structure I -2.
Experimental section
All temperature are all expressed as DEG C.All temperature are all expressed as DEG C.Unless otherwise instructed, otherwise reaction is entered under rt OK.
Use 0.2mm plates：Merck, the F of silica gel 60254Characterized to implement analytic type TLC.Use EA, Hept, DCM, MeOH Or its mixture come implement elution.Using UV or use the KMnO being subsequently heated4(3g)、K2CO3(20g), 5%NaOH (3mL) and H2O (300mL) solution is detected.
Implement CC using Brunschwig 60A silica gel (0.032-0.63mm), using EA, Hept, DCM, MeOH or it is mixed Compound implements elution.When compound contains acid functional group, 1%AcOH is added in eluant, eluent.NH for CC4OH is 25% aqueous solution.
Pass through1H-NMR (300MHz) (Varian Oxford) passes through1H-NMR(400MHz)(Bruker Advance 400) compound is characterized.Chemical shift δ is to be represented relative to solvent for use with ppm；Multiplicity：S=is unimodal, and d=is dual Peak, t=triplets, q=quartets, p=quintets, hex=sextets, hep=heptets, m=multiplets, br.=broad peaks, Coupling constant J is represented with Hz.Another selection is to be characterized by compound：LC-MS (Sciex API 2000, tool There are the binary pumps of Agilent 1100 and DAD and ELSD；Or Agilent quadrupoles MS 6140, with the binary of Agilent 1200 Pump, DAD and ELSD)；TLC (TLC plates, from Merck, the F of silica gel 60254)；Or fusing point.
Analytic type LC-MS data are obtained using following condition out of the ordinary：
● MS1 data：
ο tubing strings：Zorbax SB-Aq,3.5μm,4.6×50mm；
ο injected slurry volumes：1μL；
ο column oven temperature：40℃；
ο is detected：UV 210nm, ELSD and MS；
ο MS ionization modes：ESI+；
ο eluant, eluents：A：H2O+0.04%TFA；And B：MeCN；
ο flow velocitys：4.5mL/min；
ο gradients：5%B to 95%B (0.0min -1.0min), 95%B (1.0min -1.45min).
● MS2 data：
ο tubing strings：Zorbax Extend C18,5μm,4.6×50mm；
ο injected slurry volumes：5μL；
ο column oven temperature：40℃；
ο is detected：UV 210nm, ELSD and MS；
ο MS ionization modes：ESI-；
ο eluant, eluents：A：H2O+0.04%NH3；And B：MeCN；
ο flow velocitys：4.5mL/min；
ο gradients：5%B to 95%B (0.0min -0.75min), 95%B (0.75min -1.45min).
Implement prep-HPLC purifying on Gilson HPLC systems using following corresponding conditionses, the system equipped with The automatic samplers of Gilson 215, the pumps of Gilson 333/334, Dionex MSQ Plus detector systems and Dionex UVD340U (or Dionex DAD-3000) UV detectors：
ο tubing strings：Waters XBridge C18,10μm,30×75mm；
ο flow velocitys：75mL/min；
ο eluant, eluents：A：H2O+0.5%NH4OH；B：MeCN
ο gradients：90%A to 5%A (0.0min -3.5min), 5%A (3.5min -5.0min).
Prepare：
Prepare A：Trans -7- (4- aminomethyl-cyclohexyls amino) -1- cyclopropyl -6- fluorin-4-oxygens generation -1,4- dihydros - [1,8] naphthyridines -3- formic acid：
A.i. trans -4- (azido methyl) cyclohexylamine hydrochloride
N- [(trans) -4- (azido methyl) cyclohexyl]-amino is handled with the 4M HCl being stored in dioxane (1.2mL) Carboxylate (305mg；CAS 956352-36-6；Prepared according to WO 2007/125952 molten in) Yu dioxanes (5mL) Liquid is simultaneously further stirred overnight under rt.Gained solid is collected by filtration, is washed with absolute ether, so as to obtain 212mg (93% yield) colorless solid.
MS1(ESI,m/z)：196.40[M+MeCN+H+]；tR=0.40min.
A.ii. trans -7- (4- azido methyls-Cyclohexylamino) -1- cyclopropyl -6- fluorin-4-oxygens generation -1,4- dihydros - [1,8] naphthyridines -3- formic acid
The fluoro- 1,4- dihydros -4- oxos -1,8- naphthyridines -3- formic acid of the chloro- 1- cyclopropyl -6- of 7- is handled with DIPEA (0.58mL) (311mg；CAS 100361-18-0；It is commercially available) and mixtures of the intermediate A .i (210mg) in MeCN (7mL) and at 70 DEG C It is heated overnight.Reactant mixture is cooled to rt and solid is collected by filtration, so that it is solid to obtain 365mg (83% yield) yellow Body.
MS1(ESI,m/z)：402.19[M+H+]；tR=0.95min.
A.iii. trans -7- (4- aminomethyl-cyclohexyls amino) -1- cyclopropyl -6- fluorin-4-oxygens generation -1,4- dihydros - [1,8] naphthyridines -3- formic acid
Use PPh3Suspension of (260mg) and water (0.32mL) the processing intermediate A .ii (360mg) in THF (5mL) is simultaneously 5h is further stirred at 50 DEG C.Reactant mixture is evaporated under reduced pressure and residue is stirred in EA.Filtering gained solid, is used EA/MeOH is washed, so as to obtain 365mg (100% yield) colorless solid.
MS1(ESI,m/z)：375.17[M+H+]；tR=0.58min.
Prepare B：Trans -6- (((4- aminocyclohexyls) amino) methyl) -2H- pyridos [3,2-b] [1,4] thiazine -3 (4H) -one dihydrochloride：
B.i. trans-{ 4- [(3- oxos -3,4- dihydro -2H- pyridos [3,2-b] [1,4] thiazine -6- ylmethyls)-ammonia Base]-cyclohexyl }-carbamate：
With NaHB (OAc)3(633mg) processing N- (trans-4-amino cyclohexyl)-carbamate (214mg； CAS 177906-48-8；It is commercially available) and 3,4- dihydros -3- oxo -2H- pyridos [3,2-b] -1,4- thiazine -6- formaldehyde (225mg；CAS 443956-16-9；Prepared according to WO 2002056882) in DCM/MeOH (6:1；Suspension in 3.5mL) And 5h is further stirred under rt.With DCM and water diluted reaction mixture.Use DCM/MeOH (9:1) aqueous layer extracted.With water and The organic layer that salt water washing merges, through MgSO4Dry, filtering, evaporate under reduced pressure and pass through CC (DCM/MeOH 19:1 to 9:1 + 0.5%NH4OH) purify, so as to obtain 283mg (72% yield) colorless solid.
MS1(ESI,m/z)：393.35[M+H+]；tR=0.65min.
B.ii. trans -6- (((4- aminocyclohexyls) amino) methyl) -2H- pyridos [3,2-b] [1,4] thiazine -3 (4H) -one dihydrochloride：
Proceed since the intermediate B .i (279mg) and similar to step A A.i is prepared, obtain colorless solid title Compound (258mg；100% yield).
MS1(ESI,m/z)：293.28[M+H+]；tR=0.60min.
Prepare C：1- cyclopropyl -6- fluorin-4-oxygens generation -7- vinyl -1,4- dihydro -1,8- naphthyridines -3- benzyl chloroformates：
The chloro- 1- cyclopropyl -6- fluorin-4-oxygens generation -1,4- dihydro -1,8- naphthyridines -3- benzyl chloroformates of C.i.7-：
With benzyl bromide a-bromotoluene (1.31mL) and K2CO3The fluoro- 1,4- dihydros -4- oxos of (2.07g) processing chloro- 1- cyclopropyl -6- of 7- - 1,8- naphthyridines -3- formic acid (2.83g；It is commercially available) suspension in DMF (20mL) and heat 24h at 65 DEG C.By reaction mixing Thing is poured into waterborne and filters out gained solid, is washed with water and EA, so that it is colourless to obtain 2.60g (70% yield) after the drying Solid.
MS1(ESI,m/z)：373.27[M+H+]；tR=0.91min.
C.ii.1- cyclopropyl -6- fluorin-4-oxygens generation -7- vinyl -1,4- dihydro -1,8- naphthyridines -3- benzyl chloroformates：
With argon by intermediate C.i. (969mg), vinyl boronic acids acid anhydride pyridine complex (313mg), four-(triphenylphosphine)- Palladium (150mg) and K2CO3(431mg) is in H2(5mL) are Ji mixture in dioxane (13mL) deaerates and heats 5h under reflux O. Mixture is cooled to rt, distribute in water and EA/MeOH 9:Between 1 and filter out solid.Two layers are made to separate and use EA/ MeOH 9:1 washing aqueous phase.The organic layer merged with water and salt water washing, through MgSO4Dry and concentrate under reduced pressure and pass through CC (Hept/EA) purify, so as to obtain 120mg (13% yield) foreign body, the foreign body is to use as former state.
MS1(ESI,m/z)：365.32[M+H+]；tR=0.93min.
Prepare D：6- ((piperidin-4-yl amino) methyl) -2H- pyridos [3,2-b] [1,4] thiazine -3 (4H) -one：
D.i.64- (((3- oxos -3,4- dihydro -2H- pyridos [3,2-b] [1,4] thiazine -6- bases) methyl) amino) piperazine Pyridine -1- carboxylates：
From 4- amino -1-Boc- piperidines (401mg) and 3,4- dihydros -3- oxo -2H- pyridos [3,2-b] -1,4- thiophenes Piperazine -6- formaldehyde (450mg；CAS 443956-16-9；Prepared according to WO 2002/056882) start and similar to preparation step B B.i proceeds, and obtains yellow foam title compound (950mg；Quantitative yield).
MS1(ESI,m/z)：379.36[M+H+]；tR=0.59min.
The hydrochloric acid of D.ii.6- ((piperidin-4-yl amino) methyl) -2H- pyridos [3,2-b] [1,4] thiazine -3 (4H) -one two Salt：
Proceed since the intermediate D.i (757mg) and similar to step A A.i is prepared, obtain yellow solid title Compound (946mg；Quantitative yield).
MS1(ESI,m/z)：279.32[M+H+]；tR=0.30min.
Prepare E：7- (4- (2- amino-ethyls) piperazine -1- bases) -1- cyclopropyl -6- fluorin-4-oxygens generation -1,4- dihydros -1,8- Naphthyridines -3- formic acid：
From the fluoro- 1,4- dihydros -4- oxos -1,8- naphthyridines -3- formic acid (424mg of the chloro- 1- cyclopropyl -6- of 7-；CAS 100361-18-0；It is commercially available) and 1- piperazine ethanamines (194mg；CAS 140-31-8；It is commercially available) start and similar to preparation step A A.ii proceeds, and obtains slightly yellow solid-like title compound (655mg；100% yield).
MS1(ESI,m/z)：376.13[M-H+]；tR=0.48min.
Prepare F：7- (4- (2- amino-ethyls) piperidin-1-yl) -1- cyclopropyl -6- fluorin-4-oxygens generation -1,4- dihydros -1,8- Naphthyridines -3- carboxylic acid hydrochlorides：
F.i.7- (4- (2- ((tert-butoxycarbonyl) amino) ethyl) piperidin-1-yl) -1- cyclopropyl -6- fluorin-4-oxygens generation - 1,4- dihydro -1,8- naphthyridines -3- formic acid：
From the fluoro- 1,4- dihydros -4- oxos -1,8- naphthyridines -3- formic acid (565mg of the chloro- 1- cyclopropyl -6- of 7-；CAS 100361-18-0；It is commercially available) and N- [2- (4- piperidyls) ethyl]-carbamate (194mg；CAS 165528-81- 4；It is commercially available) start and proceed similar to step A A.ii is prepared, obtain colorless solid title compound (664mg；70% Yield).
MS1(ESI,m/z)：279.32[M+H+]；tR=0.30min.
F.ii.7- (4- (2- amino-ethyls) piperidin-1-yl) -1- cyclopropyl -6- fluorin-4-oxygens generation -1,4- dihydro -1,8- naphthalenes Pyridine -3- carboxylic acid hydrochlorides：
Proceed since the intermediate F.i (650mg) and similar to step A A.i is prepared, obtain pale-yellow solid mark Inscribe compound (571mg；100% yield).
MS1(ESI,m/z)：375.18[M+H+]；tR=0.60min.
Prepare G：1- cyclopropyl -6- fluorin-4-oxygens generation -7- ((2- (piperidin-4-yl) ethyl) amino) -1,4- dihydros -1,8- Naphthyridines -3- carboxylic acid hydrochlorides：
G.i.7- ((2- (1- (tert-butoxycarbonyl) piperidin-4-yl) ethyl) amino) -1- cyclopropyl -6- fluorin-4-oxygens generation - 1,4- dihydro -1,8- naphthyridines -3- formic acid：
From the fluoro- 1,4- dihydros -4- oxos -1,8- naphthyridines -3- formic acid (311mg of the chloro- 1- cyclopropyl -6- of 7-；CAS 100361-18-0；It is commercially available) and 4- (2- amino-ethyls) -1- piperidine carboxylic acid tertiary butyl esters (194mg；CAS 146093-46-1；City Sell) start and proceed similar to step A A.ii is prepared, obtain colorless solid title compound (240mg；46% production Rate).
MS1(ESI,m/z)：475.27[M+H+]；tR=0.95min.
G.ii.1- cyclopropyl -6- fluorin-4-oxygens generation -7- ((2- (piperidin-4-yl) ethyl) amino) -1,4- dihydro -1,8- naphthalenes Pyridine -3- carboxylic acid hydrochlorides：
Proceed since the intermediate G.i (237mg) and similar to step A A.i is prepared, obtain colorless solid title Compound (235mg；100% yield).
MS1(ESI,m/z)：375.17[M+H+]；tR=0.57min.
Prepare H：6- (((piperidin-4-ylmethyl) amino) methyl) -2H- pyridos [3,2-b] [1,4] thiazine -3 (4H) - Keto hydrochloride：
H.i.4- ((((3- oxos -3,4- dihydro -2H- pyridos [3,2-b] [1,4] thiazine -6- bases) methyl) amino) first Base) piperidines -1- carboxylates：
From 1-Boc- (4- amino methyls) piperidines (214mg) and 3,4- dihydro -3- oxo -2H- pyridos [3,2-b] -1, 4- thiazine -6- formaldehyde (225mg；CAS 443956-16-9；Prepared according to WO 2002/056882) start and similar to preparation B Step B.i proceeds, and obtains yellow foam title compound (387mg；98% yield).
MS1(ESI,m/z)：393.34[M+H+]；tR=0.62min.
H.ii.6- (((piperidin-4-ylmethyl) amino) methyl) -2H- pyridos [3,2-b] [1,4] thiazine -3 (4H) -one Hydrochloride：
Proceed since the intermediate H.i (381mg) and similar to step A A.i is prepared, obtain slightly yellow solid-like mark Inscribe compound (395mg；Quantitative yield).
MS1(ESI,m/z)：293.29[M+H+]；tR=0.35min.
Prepare I：7- ((4- (amino methyl) piperidin-1-yl) methyl) -1- cyclopropyl -6- fluorin-4-oxygens generation -1,4- dihydros - 1,8- naphthyridines -3- carboxylic acid hydrochlorides：
I.i.1- cyclopropyl -6- fluorin-4-oxygens generation -7- vinyl -1,4- dihydro -1,8- naphthyridines -3- formic acid
From the fluoro- 1,4- dihydros -4- oxos -1,8- naphthyridines -3- formic acid (4.23g of the chloro- 1- cyclopropyl -6- of 7-；It is commercially available) and second Ene boric acid acid anhydride pyridine complex (1.80g, commercially available) starts and proceeded similar to step C C.ii is prepared, and obtains slightly yellow Solid-like title compound (1.99g；Crude material, 50% yield).
1H NMR(DMSO d-6)δ：8.81 (s, 1H), 8.48 (d, J=9.4Hz, 1H), 7.18 (ddd, J1=17.1Hz, J2=10.7Hz, J3=1.6Hz, 1H), 6.76 (dd, J1=17.1Hz, J2=1.9Hz, 1H), 5.97 (dd, J1=10.7Hz, J2 =1.9Hz, 1H), 3.87 (m, 1H), 1.20 (m, 4H)
I.ii.1- cyclopropyl -7- (1,2- dihydroxy ethyls) -6- fluorin-4-oxygens generation -1,4- dihydro -1,8- naphthyridines -3- formic acid
With NMO (989mg) and K2OsO4·2H2O (22.5mg) processing intermediate compound I .i (1.67g) are in DCM/H2O(3:1； Solution in 61mL) and the vigorous stirring overnight under rt.By reactant mixture distribution in water and DCM/MeOH (9:1) between.Point From organic layer.With DCM/MeOH (9:1) washing water layer and the organic layer merged with salt water washing, through MgSO4Dry and in decompression Lower concentration.With EA/ triturated under ether residues, filtering is washed with EA/ ether and dried under HV, so as to obtain 1.53g (81% Yield) beige solid.
MS1(ESI,m/z)：309.09[M+H+]；tR=0.53min.
The fluoro- 7- formoxyls -4- oxos -1,4- dihydros -1,8- naphthyridines -3- formic acid of I.iii.1- cyclopropyl -6-
Use NaIO4The solution processing intermediate compound I .ii (1.54g) of (2.46g) in water (20mL) is in acetone (30mL) Suspension.Mixture is stirred overnight under rt.Reactant mixture is filtered, and concentrates filtrate under reduced pressure.Residue is distributed In DCM/MeOH (9:1) between water.Two are made to be separated and with salt water washing organic layer, through MgSO4Dry, filter and dense Contracting.With EA/ triturated under ether residues, filtering is washed with EA/ ether and dried under HV, so as to obtain 270mg (20% yield) Slightly yellow solid.
MS1(ESI,m/z)：295.08[M+H2O+H+]；tR=0.53min.
I.iv.7- ((4- (((tert-butoxycarbonyl) amino) methyl) piperidin-1-yl) methyl) fluoro- 4- of -1- cyclopropyl -6- Oxo -1,4- dihydro -1,8- naphthyridines -3- formic acid
Opened from intermediate compound I .iii (230mg) and N- (4- piperidino methyls) carbamate (107mg, commercially available) Begin and proceed similar to step B B.i is prepared, obtain gray solid shape title compound (60mg；25% yield).
MS1(ESI,m/z)：475.29[M+H+]；tR=0.54min.
I.v.7- ((4- (amino methyl) piperidin-1-yl) methyl) -1- cyclopropyl -6- fluorin-4-oxygens generation -1,4- dihydro -1, 8- naphthyridines -3- carboxylic acid hydrochlorides
Intermediate compound I .iv is handled (in 57mg) Yu dioxanes (0.6mL) with the 4M HCl being stored in dioxane (0.12mL) Solution simultaneously further stirs 24h under rt.Solid is collected by filtration, is washed and is dried under HV with ether and DCM, so that To 47mg (99% yield) gray solid.
MS1(ESI,m/z)：375.14[M+H+]；tR=0.38min
Prepare J：((3- oxos -3,4- dihydro -2H- pyridos [3,2-b] [1,4] thiazine -6- bases) methyl) (2- oxo second Base) carbamate：
J.i. racemic-(2,3- dihydroxy-propyl group)-(3- oxos -3,4- dihydro -2H- pyridos [3,2-b] [1,4] thiophene Piperazine -6- ylmethyls)-carbamate
With AcOH (3 drop) processing 3- amido-1,2-propanediols (0.24mL) and 3,4- dihydro -3- oxo -2H- pyridos [3,2-b] -1,4- thiazine -6- formaldehyde (583mg；CAS 443956-16-9；Prepared according to WO2002/056882) in DCM/ EtOH(1:1；Mixture in 20mL) simultaneously stirs 5h under rt.NaBH is added at 0 DEG C4(113mg) and continue stirring 30min.Reactant mixture is quenched by the way that 1N HCl are added dropwise, NaHCO is then used3Saturated aqueous solution is neutralized, and uses BOC2O (1.31g) processing is simultaneously further stirred 2 days under rt.By mixture distribution in DCM and saturation NaHCO3Between the aqueous solution.To have Machine layer is through MgSO4Dry, concentrate under reduced pressure and pass through CC (EA to EA/MeOH 9:1) residue is purified, so as to obtain 1.37g (quantitative yield) slightly yellow foam.
MS1(ESI,m/z)：370.07[M+H+]；tR=0.64min.
J.ii. ((3- oxos -3,4- dihydro -2H- pyridos [3,2-b] [1,4] thiazine -6- bases) methyl) (2- oxo second Base) carbamate
Use NaIO4The solution of (802mg) in water (6mL) handles intermediate J.i (1.11g) in acetone (12mL) dropwise Solution.30min is stirred the mixture under rt.Filter out solid and washed with EA.Organic layer is washed with weak brine, is passed through MgSO4Dry and concentrate under reduced pressure, so as to obtain 730mg (72% yield) yellow foam, it is directly used in next step In.
MS1(ESI,m/z)：282.00[M+H+]；tR=0.64-0.75min (broad peak).
Prepare K：Trans -4- repeatedly nitrogen bases methyl-cyclohexyl base amine
K.i. (trans -4- (azido methyl) cyclohexyl) carbamate
Sodium azide (1.64g) is added to N- [trans -4- [[(methyl sulphonyl) epoxide] methyl] cyclohexyl]-amino Carboxylate (7.1g, CAS 683269-95-6；Prepared according to WO 2012/101013) solution in DMF (80mL) In.Suspension is stirred into 4h at 55 DEG C.Reactant mixture is set to be cooled to rt and be diluted with water and EA.Make two layer separation.With Aqueous phase is extracted twice by EA.The organic layer merged with water (2 ×) and salt water washing, through MgSO4Dry, and concentrate under reduced pressure. Residue is purified by CC (Hept/EA), so as to obtain colorless solid title compound (4.15g, 71%).
1H NMR(CDCl3)δ：4.32-4.48 (m, 1H), 3.24-3.44 (m, 1H), 3.12 (d, J=6.7Hz, 2H), 1.96-2.10(m,2H),1.73-1.86(m,2H),1.42(s,9H),0.97-1.17(m,4H)。
K.ii. trans 4- azido methyls-cyclo-hexylamine
(4M that is stored in dioxane (31mL) is added dropwise in the solution in 4.1g) Yu dioxanes (81mL) to K.i is prepared HCl.Reactant mixture is stirred overnight under rt.Mixture is concentrated under reduced pressure and by residue distribution in water and DCM/MeOH (9:1) between.Make two layer separation.Abandon organic phase.Use NH4OH alkalizes water layer to pH about 9 and with DCM/MeOH (9:1) wash Wash 3 times.By the organic phase of merging through MgSO4Dry, filter and concentrate under reduced pressure, so as to obtain yellow liquid title compound Thing (1.82g, 73% yield), it is to use as former state.
1H NMR(CDCl3)δ：3.13 (d, J=6.6Hz, 2H), 2.50-2.68 (m, 1H), 1.69-1.96 (m, 4H), 1.38-1.60(m,1H),0.92-1.19(m,4H)。
Prepare L：The fluoro- 1- methyl -4- oxos -1,4- dihydros of trans -7- (4- aminomethyl-cyclohexyls amino) -6--[1, 8] naphthyridines -3- formic acid
L.i. the fluoro- 1- methyl -4- oxos -1,4- dihydros of trans -7- (4- azido methyls-Cyclohexylamino) -6--[1, 8] naphthyridines -3- formic acid
By the fluoro- 1,4- dihydros -1- methyl -4- oxos -1,8- naphthyridines -3- formic acid (513mg of the chloro- 6- of 7-；CAS 1279121- 43-5, is prepared according to WO 2011/037433) and K product (308mg) and DIPEA (0.72mL) are prepared in MeCN (10mL) Mixture be heated overnight at 70 DEG C.Filtering reactant mixture simultaneously washs solid with MeCN.Mother liquor is evaporated under reduced pressure and is incited somebody to action Residue is stirred with MeCN/ ether/MeOH and solid is collected by filtration.Merge two batches cutting and be dried under reduced pressure, from And obtain 684mg (91% yield) yellow solid
1H NMR(DMSO)δ：8.85 (s, 1H), 8.14 (d, J=7.3Hz, 1H), 7.91 (d, J=10.6Hz, 1H), 3.91 (s, 3H), 3.25 (d, J=6.4Hz, 2H), 1.94-2.07 (m, 2H), 1.74-1.86 (m, 2H), 1.33-1.61 is (overlapping m,2H),1.21-1.30(m,2H),1.04-1.20(m,2H)。
L.ii. trans -7- (4- aminomethyl-cyclohexyls amino) -6- fluoro- 1- methyl -4- oxos -1,4- dihydros-[1,8] Naphthyridines -3- formic acid
By PPh3(505mg) and water (0.63mL) are added to suspensions of the intermediate L.i (655mg) in THF (10.5mL) In liquid, and mixture is heated into 5h at 50 DEG C.Volatile matter is removed under reduced pressure and residue is stirred in EA/MeOH.Pass through Solid is collected by filtration, is washed and is dried under HV with EA/MeOH, so as to obtain 587mg whitish powder shapes thing (96% yield).
1H NMR(DMSO)δ：8.84 (s, 1H), 8.11 (d, J=7.3Hz, 1H), 7.89 (d, J=10.7Hz, 1H), 3.83-4.05 (overlapping m, 1H), 3.90 (s, 3H), 2.40 (d, J=6.1Hz, 2H), 1.92-2.05 (m, 2H), 1.76-1.89 (m,2H),1.29-1.50(m,2H),1.10-1.29(m,1H),0.89-1.10(m,2H)。
Prepare M：Trans -7- (4- aminomethyl-cyclohexyls amino) -1- ethyl -6- fluorin-4-oxygens generation -1,4- dihydros-[1, 8] naphthyridines -3- formic acid
M.i. trans -7- (4- azido methyls-Cyclohexylamino) -1- ethyl -6- fluorin-4-oxygens generation -1,4- dihydros-[1, 8] naphthyridines -3- formic acid
By the fluoro- 1,4- dihydros -4- oxos -1,8- naphthyridines -3- formic acid (4.51mg of the chloro- 1- ethyls -6- of 7-；CAS 79286- 73；Prepared according to EP 27752), to prepare K compound (46.3mg) and DIPEA (0.108mL) mixed in MeCN (1.5mL) Compound is heated overnight at 70 DEG C.Mixture is set to be cooled to rt and be diluted with water.Filtering gained solid is simultaneously stirred in EA, so that Obtain 105mg (91% yield) brown solid.The product is used in next step as former state.
1H NMR(DMSO)δ：8.88 (s, 1H), 8.16 (d, J=8.2Hz, 1H), 7.91 (d, J=10.6Hz, 1H), 4.46 (q, J=7.0Hz, 2H), 3.83-4.02 (m, 1H), 3.25 (d, J=6.4Hz, 2H), 1.92-2.06 (m, 2H), 1.73- 1.88 (m, 2H), 1.31-1.62 (m, 3H), 1.36 (t, J=7.0Hz, 3H), 1.04-1.23 (m, 2H).
M.ii. trans -7- (4- aminomethyl-cyclohexyls amino) -1- ethyl -6- fluorin-4-oxygens are for -1,4- dihydro-[1,8] Naphthyridines -3- formic acid
By PPh3(72mg) and water (0.108mL) are added to suspension of the intermediate M.i (97mg) in THF (1.8mL) In.Reactant mixture is heated into 5h at 50 DEG C, rt is reached and evaporates under reduced pressure.Residue, mistake are stirred with EA/MeOH Filter, is washed with EA/MeOH and is dried under HV, so as to obtain 90mg (100% yield) beige solid.The product is used for as former state In next step.
MS1(ESI,m/z)：362.99[M+H+]；tR=0.57min.
Prepare N 7- [4- (2- amino-ethyls)-piperidin-1-yl] -6- fluoro- 1- methyl -4- oxos -1,4- dihydros-[1,8] Naphthyridines -3- formic acid
N.i 7- (4- (2- ((tert-butoxycarbonyl) amino) ethyl) piperidin-1-yl) fluoro- 1- methyl -4- oxo -1 of -6-, 4- dihydro -1,8- naphthyridines -3- formic acid
By the fluoro- 1,4- dihydros -1- methyl -4- oxos -1,8- naphthyridines -3- formic acid (228mg of the chloro- 6- of 7-；CAS 1279121- 43-5, is prepared according to WO 2011037433), 4- (2-Boc- amino-ethyls) piperidines (203mg, commercially available) and DIPEA (0.32mL) Mixture in MeCN (5.34mL) is heated overnight at 70 DEG C.Mixture is cooled to rt, filter out sediment, use MeCN Wash and dried under HV, so as to obtain 248mg (62% yield) white solid.
MS1(ESI,m/z)：448.98[M+H+]；tR=0.92min.
N.ii.7- [4- (2- amino-ethyls)-piperidin-1-yl] -6- fluoro- 1- methyl -4- oxos -1,4- dihydros-[1,8] Naphthyridines -3- formic acid
(it is added dropwise in the suspension in 238mg) Yu dioxanes (2mL) to intermediate N.i and is stored in dioxane (0.53mL) In 4M HCl.Reactant mixture is stirred into 5h under rt, H is used2O and EA/MeOH (9:1) dilute.It is used in combination two phase separations EA/MeOH washes twice aqueous phase.By adding NH4OH is adjusted the pH of aqueous phase to pH about 7 and concentrate solution under reduced pressure.With DCM/MeOH(4:1) residue is stirred, filters and is purified by HPLC (alkalescence), so that it is light yellow solid to obtain 170mg (92%) Body.
MS1(ESI,m/z)：348.97[M+H+]；tR=0.57min.
Example
Example 1：Anti-form-1-cyclopropyl-6- fluorin-4-oxygens generation-7- (4- [(3- oxo-3,4- dihydro-2H- pyridos [3, 2-b] [1,4] thiazine -6- ylmethyls)-amino]-methyl }-Cyclohexylamino) -1,4- dihydros-[1,8] naphthyridines -3- formic acid：
With NaHB (OAc)3(101mg) processing prepares A compound (60mg) and 3,4- dihydro -3- oxo -2H- pyridos [3,2-b] -1,4- thiazine -6- formaldehyde (36mg；CAS 443956-16-9；Prepared according to WO 2002056882) in DCM/MeOH (4:1；Suspension in 0.6mL) and the further stirring 5h under rt.With DCM and water diluted reaction mixture.Use DCM/ MeOH(9:1) aqueous layer extracted.The organic layer merged with water and salt water washing, through MgSO4Dry, filtering is evaporated simultaneously under reduced pressure Purified by prep HPLC, so as to obtain 47mg (53% yield) colorless solid.
MS1(ESI,m/z)：553.27[M+H+]；tR=0.66min.
Example 2：Anti-form-1-cyclopropyl-6- fluorin-4-oxygens generation-7- { 4- [(3- oxo-3,4- dihydro-2H- pyridos [3,2- B] [1,4] thiazine -6- ylmethyls)-amino]-Cyclohexylamino } -1,4- dihydros-[1,8] naphthyridines -3- formic acid
The fluoro- 1,4- dihydros -4- oxos -1,8- naphthyridines -3- formic acid of the chloro- 1- cyclopropyl -6- of 7- is handled with DIPEA (0.27mL) (82mg；CAS 100361-18-0；It is commercially available) and mixture of the intermediate B (110mg) in NMP (1.8mL) and at 100 DEG C Heat 4h.Reactant mixture is cooled to rt, diluted with ether and solid is collected by filtration, so as to pass through prep HPLC 5mg (3% yield) beige solid is obtained after purification.
MS2(ESI,m/z)：537.18[M-H+]；tR=0.52min.
1- cyclopropyl -6- the fluorin-4-oxygens of example 3 generation -7- (2- { 4- [(3- oxo -3,4- dihydro -2H- pyridos [3,2-b] [1,4] thiazine -6- ylmethyls)-amino]-piperidin-1-yl }-ethyl) -1,4- dihydros-[1,8] naphthyridines -3- formic acid：
3.i.1- cyclopropyl -6- fluorin-4-oxygens generation -7- (2- { 4- [(3- oxo -3,4- dihydro -2H- pyridos [3,2-b] [1,4] thiazine -6- ylmethyls)-amino]-piperidin-1-yl }-ethyl) -1,4- dihydros-[1,8] naphthyridines -3- benzyl chloroformates
With 1,1,3,3- TMGs (0.01mL) processing intermediate C (109mg), intermediate D (105mg) and TEA The suspension of (0.1mL) in DMF (0.6mL) and the further stirring 6h at 90 DEG C.Reactant mixture is set to reach rt, it is dilute with water Release and use EA/MeOH (9:1；3 ×) extract.The organic layer merged with water and salt water washing, through MgSO4Dry, filtering, in decompression It is lower to evaporate and pass through CC (DCM/MeOH, 19:1 to 9:1) purify, so as to obtain 70mg (36% yield) light brown foam.
MS1(ESI,m/z)：643.35[M+H+]；tR=0.60min.
3.ii.1- cyclopropyl -6- fluorin-4-oxygens generation -7- (2- { 4- [(3- oxo -3,4- dihydro -2H- pyridos [3,2-b] [1,4] thiazine -6- ylmethyls)-amino]-piperidin-1-yl }-ethyl) -1,4- dihydros-[1,8] naphthyridines -3- formic acid
By intermediate 3.i (64mg) in AcOH (0.8mL) and HBr (62% aqueous solution；Solution in 0.05mL) is under rt It is stirred overnight.Use DCM/MeOH (9:1) diluted reaction mixture and NH is used4The OH aqueous solution dilutes.Organic layer is separated, is used in combination DCM/MeOH(9:1) aqueous layer extracted.The organic layer merged with salt water washing, through MgSO4Dry, filtering is evaporated simultaneously under reduced pressure Purified by prep HPLC, so as to obtain 4mg (7% yield) colorless solid.
MS1(ESI,m/z)：553.24[M+H+]；tR=0.50min.
Example 4：1- cyclopropyl -6- fluorin-4-oxygens generation -7- (4- { 2- [(3- oxo -3,4- dihydro -2H- pyridos [3,2-b] [1,4] thiazine -6- ylmethyls)-amino]-ethyl }-piperazine -1- bases) -1,4- dihydros-[1,8] naphthyridines -3- formic acid：
From intermediate E (75mg) and 3,4- dihydros -3- oxo -2H- pyridos [3,2-b] -1,4- thiazine -6- formaldehyde (45mg；CAS 443956-16-9；Prepared according to WO 2002056882) start and proceed similar to example 1, obtain micro- Yellow solid title compound (40mg；36% yield).
MS2(ESI,m/z)：552.17[M-H+]；tR=0.50min.
Example 5：1- cyclopropyl -6- fluorin-4-oxygens generation -7- (4- { 2- [(3- oxo -3,4- dihydro -2H- pyridos [3,2-b] [1,4] thiazine -6- ylmethyls)-amino]-ethyl }-piperidin-1-yl) -1,4- dihydros-[1,8] naphthyridines -3- formic acid：
From intermediate F (66mg) and 3,4- dihydros -3- oxo -2H- pyridos [3,2-b] -1,4- thiazine -6- formaldehyde (36mg；CAS 443956-16-9；Prepared according to WO 2002056882) start and proceed similar to example 1, obtain nothing Color solid-like title compound (49mg；55% yield).
MS1(ESI,m/z)：553.27[M+H+]；tR=0.68min.
Example 6：1- cyclopropyl -6- fluorin-4-oxygens generation -7- { 2- [1- (3- oxo -3,4- dihydro -2H- pyridos [3,2-b] [1,4] thiazine -6- ylmethyls)-piperidin-4-yl]-ethylamino } -1,4- dihydros-[1,8] naphthyridines -3- formic acid：
From intermediate G (72mg) and 3,4- dihydros -3- oxo -2H- pyridos [3,2-b] -1,4- thiazine -6- formaldehyde (36mg；CAS 443956-16-9；Prepared according to WO 2002056882) start and proceed similar to example 1, obtain micro- Yellow solid title compound (37mg；42% yield).
MS1(ESI,m/z)：553.32[M+H+]；tR=0.65min.
Example 7：1- cyclopropyl -6- fluorin-4-oxygens generation -7- (4- { [(3- oxo -3,4- dihydro -2H- pyridos [3,2-b] [1,4] thiazine -6- ylmethyls)-amino]-methyl }-piperidin-1-yl) -1,4- dihydros-[1,8] naphthyridines -3- formic acid：
The fluoro- 1,4- dihydros -4- oxos -1,8- naphthyridines -3- formic acid of the chloro- 1- cyclopropyl -6- of 7- is handled with DIPEA (0.27mL) (127mg；CAS 100361-18-0；It is commercially available) and mixtures of the intermediate H (168mg) in MeCN (3mL) and at 70 DEG C plus Hot 3h.Reactant mixture is cooled to rt and solid is collected by filtration, so as to obtain 202mg (83% yield) colorless solid.
MS2(ESI,m/z)：537.12[M-H+]；tR=0.53min.
Example 8：Anti-form-1-cyclopropyl-6- fluorin-4-oxygens generation-7- (4- [(3- oxo-3,4- dihydro-2H- pyridos [3, 2-b] [1,4] oxazine -6- ylmethyls)-amino]-methyl }-Cyclohexylamino) -1,4- dihydros-[1,8] naphthyridines -3- formic acid：
From intermediate A (45mg) and 3,4- dihydros -3- oxo -2H- pyridos [3,2-b] -1,4- oxazine -6- formaldehyde (27mg；CAS 443956-11-4；Prepared according to WO 2002056882) start and proceed similar to example 1, obtain nothing Powdered title compound (the 27mg of color；34% yield).
MS1(ESI,m/z)：537.24[M+H+]；tR=0.65min.
Example 9：1- cyclopropyl -6- fluorin-4-oxygens generation -7- (4- { [(3- oxo -3,4- dihydro -2H- pyridos [3,2-b] [1,4] thiazine -6- ylmethyls)-amino]-methyl }-piperidin-1-yl methyl) -1,4- dihydros-[1,8] naphthyridines -3- formic acid：
From intermediate compound I (45mg) and 3,4- dihydros -3- oxo -2H- pyridos [3,2-b] -1,4- thiazine -6- formaldehyde (25mg；CAS 443956-16-9；Prepared according to WO2002/056882) start and proceed similar to example 1, obtain nothing Powdered title compound (the 15mg of color；25% yield).
MS1(ESI,m/z)：553.20[M+H+]；tR=0.48min.
Example 10：1- cyclopropyl -6- fluorin-4-oxygens generation -7- { 4- [(3- oxo -3,4- dihydro -2H- pyridos [3,2-b] [1,4] thiazine -6- ylmethyls)-amino]-piperidin-1-yl } -1,4- dihydros-[1,8] naphthyridines -3- formic acid：
From the fluoro- 1,4- dihydros -4- oxos -1,8- naphthyridines -3- formic acid of the chloro- 1- cyclopropyl -6- of intermediate D (337mg) and 7- (240mg；CAS 100361-18-0；It is commercially available) start and proceed similar to example 7, obtain slightly yellow solid-like titled Compound (342mg；77% yield).
MS1(ESI,m/z)：525.22[M+H+]；tR=0.65min.
Example 11：1- cyclopropyl -6- fluorin-4-oxygens generation -7- (4- { 2- [(3- oxo -3,4- dihydro -2H- pyridos [3,2- B] [1,4] thiazine -6- ylmethyls)-amino]-ethyl }-piperazine -1- bases) -1,4- dihydro-quinoline -3- formic acid：
With NaHB (OAc)3(170mg) handles 1- cyclopropyl -6- fluoro- 1,4- dihydros -4- oxos -7- (1- piperazinyls) -3- Quinolinecarboxylic acid (133mg；CAS 85721-33-1；It is commercially available) and intermediate J (135mg) in DCM/MeOH (3:1；It is outstanding in 4mL) Supernatant liquid and the further stirring 30min under rt.By reactant mixture distribution in DCM and saturation NaHCO3Between the aqueous solution.Use DCM Aqueous layer extracted.By the organic layer of merging through MgSO4Dry and concentrate under reduced pressure.Residue is dissolved in dioxane (2mL), Handled and be further stirred overnight under rt with the 4N HCl being stored in dioxane (1mL).Yong dioxane diluted reaction mixture, Filtering.Residue is dissolved in saturation NaHCO3The aqueous solution and DCM/MeOH (9:1) in, by organic layer through MgSO4Dry and subtracting Pressure concentration, so as to obtain 88mg (40% yield) slightly yellow solid after being crystallized from EA/MeOH.
MS1(ESI,m/z)：553.23[M+H+]；tR=0.56min.
Example 12：1- cyclopropyl -6- fluorin-4-oxygens generation -7- (4- { 2- [(3- oxo -3,4- dihydro -2H- pyridos [3,2- B] [1,4] oxazine -6- ylmethyls)-amino]-ethyl }-piperazine -1- bases) -1,4- dihydros-[1,8] naphthyridines -3- formic acid
From the compound (75mg) and 3- oxos -3,4- dihydro -2H- pyridos [3,2-b] [1,4] oxazine -6- first for preparing E Aldehyde (36mg；CAS 443956-11-4；It is commercially available) start and proceed similar to example 1, by prep-HPLC after purification Obtain colorless solid title compound (30mg；30% yield).
1H NMR(DMSO)δ：8.59 (s, 1H), 8.05 (d, J=13.6Hz, 1H), 7.28 (d, J=8.1Hz, 1H), 6.98 (d, J=8.1Hz, 1H), 4.59 (s, 2H), 3.80-3.91 (m, 4H), 3.60-3.74 (overlapping m, 1H), 3.66 (s, 2H), 2.62 (t, J=6.6Hz, 2H), 2.46-2.55 (overlapping m, 4H), 2.39-2.46 (overlapping m, 2H), 1.12-1.22 (m, 2H),1.00-1.12(m,2H).MS1(ESI,m/z)：538.29[M+H+]；tR=0.56min.
Example 13：The trans fluoro- 1- methyl -4- oxos -7- of -6- (4- { [(3- oxo -3,4- dihydro -2H- pyridos [3,2- B] [1,4] thiazine -6- ylmethyls)-amino]-methyl }-Cyclohexylamino) -1,4- dihydros-[1,8] naphthyridines -3- formic acid
From the compound (60mg) and 3,4- dihydros -3- oxo -2H- pyridos [3,2-b] -1,4- thiazine -6- first for preparing L Aldehyde (31mg；CAS 443956-16-9；Prepared according to WO 2002056882) start and proceed similar to example 1, logical Cross prep-HPLC and obtain white solid title compound (32mg after purification；41% yield).
1H NMR(DMSO)δ：10.81 (s, 1H), 8.85 (s, 1H), 8.09-8.17 (m, 1H), 7.91 (d, J= 10.7Hz, 1H), 7.71 (d, J=7.8Hz, 1H), 7.07 (d, J=7.8Hz, 1H), 3.86-4.06 (overlapping m, 1H), 3.90 (s, 3H), 3.66 (s, 2H), 3.50 (s, 2H), 2.37 (d, J=6.4Hz, 2H), 1.92-2.04 (m, 2H), 1.80-1.92 (m, 2H),1.31-1.50(m,3H),0.93-1.14(m,2H)。
MS1(ESI,m/z)：527.15[M+H+]；tR=0.63min.
Example 14：The trans fluoro- 1- methyl -4- oxos -7- of -6- (4- { [(3- oxo -3,4- dihydro -2H- pyridos [3,2- B] [1,4] oxazine -6- ylmethyls)-amino]-methyl }-Cyclohexylamino) -1,4- dihydros-[1,8] naphthyridines -3- formic acid
From the compound (70mg) and 3- oxos -3,4- dihydro -2H- pyridos [3,2-b] [1,4] oxazine -6- first for preparing L Aldehyde (40mg；CAS 443956-11-4；It is commercially available) start and proceed similar to example 1, by prep-HPLC after purification Obtain white solid title compound (19mg；19% yield).
1H NMR(DMSO)δ：8.85 (s, 1H), 8.16 (s, 1H), 8.13 (d, J=7.6Hz, 1H), 7.91 (d, J= 10.7Hz, 1H), 7.30 (d, J=8.0Hz, 1H), 7.01 (d, J=8.0Hz, 1H), 4.60 (s, 2H), 3.86-4.08 is (overlapping M, 1H), 3.90 (s, 3H), 3.70 (s, 2H), 2.36-2.47 (overlapping m, 2H), 1.92-2.05 (m, 2H), 1.81-1.92 (m, 2H),1.32-1.51(m,3H),0.93-1.14(m,2H)。
MS1(ESI,m/z)：511.06[M+H+]；tR=0.61min.
Example 15：Anti-form-1-ethyl-6- fluorin-4-oxygens generation-7- (4- { [(3- oxo-3,4- dihydro-2H- pyridos [3,2- B] [1,4] thiazine -6- ylmethyls)-amino]-methyl }-Cyclohexylamino) -1,4- dihydros-[1,8] naphthyridines -3- formic acid
From the compound (73mg) and 3,4- dihydros -3- oxo -2H- pyridos [3,2-b] -1,4- thiazine -6- first for preparing M Aldehyde (43mg；CAS 443956-16-9；Prepared according to WO 2002056882) start and proceed similar to example 1, use NaBH4Rather than NaHB (OAc)3, obtaining white solid title compound (52mg after purification by prep-HPLC；48% production Rate).1H NMR(DMSO)δ：10.81 (s, 1H), 8.87 (s, 1H), 8.14 (d, J=7.4Hz, 1H), 7.90 (d, J= 10.7Hz, 1H), 7.71 (d, J=7.9Hz, 1H), 7.06 (d, J=7.9Hz, 1H), 4.44 (q, J=6.4Hz, 2H), 3.81- 4.02 (m, 1H), 3.66 (s, 2H), 3.50 (s, 2H), 2.37 (d, J=6.4Hz, 2H), 1.92-2.04 (m, 2H), 1.81- 1.92 (m, 2H), 1.29-1.52 (overlapping m, 3H), 1.36 (t, J=7.0Hz, 3H), 0.91-1.14 (m, 2H).
MS1(ESI,m/z)：541.05[M+H+]；tR=0.53min.
Example 16：The fluoro- 1- methyl -4- oxos -7- of 6- (4- { 2- [(3- oxo -3,4- dihydro -2H- pyridos [3,2-b] [1,4] oxazine -6- ylmethyls)-amino]-ethyl }-piperidin-1-yl) -1,4- dihydros-[1,8] naphthyridines -3- formic acid
From the compound (359mg) and 3- oxos -3,4- dihydro -2H- pyridos [3,2-b] [1,4] oxazine -6- for preparing N Formaldehyde (183mg；CAS 443956-11-4；It is commercially available) start and proceed similar to example 1, purified by prep-HPLC White solid title compound (123mg is obtained afterwards；23% yield).
1H NMR(DMSO)δ：11.17 (s, 1H), 8.94 (s, 1H), 8.03 (d, J=13.7Hz, 1H), 7.31 (d, J= 8.0Hz, 1H), 7.01 (d, J=8.0Hz, 1H), 4.61 (s, 2H), 4.50 (d, J=13.0Hz, 2H), 3.93 (s, 3H), 3.39 (q, J=7.0Hz, 2H), 3.14 (t, J=12.6Hz, 2H), 2.52-2.61 (overlapping m, 2H), 1.65-1.88 (m, 3H), 1.40 (q, J=6.6Hz, 2H), 1.16-1.31 (m, 2H).
MS1(ESI,m/z)：511.03[M+H+]；tR=0.62min.
Example 17：The fluoro- 1- methyl -4- oxos -7- of 6- (4- { 2- [(3- oxo -3,4- dihydro -2H- pyridos [3,2-b] [1,4] thiazine -6- ylmethyls)-amino]-ethyl }-piperidin-1-yl) -1,4- dihydros-[1,8] naphthyridines -3- formic acid
From the compound (63mg) and 3,4- dihydros -3- oxo -2H- pyridos [3,2-b] -1,4- thiazine -6- first for preparing N Aldehyde (40mg；CAS 443956-16-9；Prepared according to WO 2002056882) start and proceed similar to example 1, logical Cross prep-HPLC after purification, obtain white solid title compound (33mg；35% yield).
1H NMR(DMSO)δ：10.81 (s, 1H), 8.90 (s, 1H), 8.00 (d, J=13.7Hz, 1H), 7.70 (d, J= 7.9Hz, 1H), 7.05 (d, J=7.8Hz, 1H), 4.40-4.54 (m, 2H), 3.90 (s, 3H), 3.66 (s, 2H), 3.50 (s, 2H), 3.11 (t, J=12.9Hz, 2H), 2.53 (t, J=7.0Hz, 2H), 1.64-1.84 (m, 3H), 1.32-1.46 (m, 2H), 1.10-1.31(m,2H)。
MS1(ESI,m/z)：526.94[M+H+]；tR=0.64min.
The pharmacological property of the compounds of this invention
Ex vivo assay
Bacterial growth MIC：
Experimental method：
" Methods for are followed by micro-dilution method in the Mueller-Hinton meat soups that cation is adjusted Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically ", Recognized Standards, the 7th edition, Clinical and Laboratory Standards Institute (CLSI) Illustrated given in Document M7-A7, Wayne, PA, USA, 2006 and determine MIC (MIC；mg/l).
As a result：
All Compound of Example are tested for some Gram-positives and especially gramnegative bacterium.Below Exemplary antibacterial test result is provided in table 1 (MIC is represented with mg/L).Staphylococcus aureus A798, Klebsiella pneumoniae A651 and Acinetobacter baumannii T6474 are multi-resistant strain (especially quinolone resistants), and moraxelle catarrhalis A894 and large intestine bar Bacterium (E.coli) ATCC 25922 is quinolone sensitive strains.
Table 1

Claims (16)

1. a kind of compound of formula I,
Wherein
R1Represent (C1-C3) alkyl or (C3-C5) cycloalkyl；
U represents CH or N；
V represents O or S；And
A represents the group in following group：
Or its pharmaceutically acceptable salt.
2. compound of formula I as claimed in claim 1, wherein
R1Represent methyl or ethyl；Or R1Represent cyclopropyl；
U represents CH or N；
V represents O or S；
And
A represents the group in following group：
Wherein
D represents key or CH2；And
E represents key, CH2Or CH2CH2；
Or its pharmaceutically acceptable salt.
3. compound of formula I as claimed in claim 2, wherein R1Represent methyl；
Or its pharmaceutically acceptable salt.
4. compound of formula I as claimed in claim 2, wherein R1Represent cyclopropyl；
Or its pharmaceutically acceptable salt.
5. the compound of formula I as any one of Claims 1-4, wherein V represent S；
Or its pharmaceutically acceptable salt.
6. the compound of formula I as any one of Claims 1-4, wherein U represent N；
Or its pharmaceutically acceptable salt.
7. the compound of formula I as any one of Claims 1-4, wherein A represent the group in following group：
Or its pharmaceutically acceptable salt.
8. compound as claimed in claim 1, it is selected from：
1- cyclopropyl -6- fluorin-4-oxygens generation -7- (4- { [(3- oxos -3,4- dihydro -2H- pyridos [3,2-b] [1,4] thiazine -6- Ylmethyl)-amino]-methyl }-Cyclohexylamino) -1,4- dihydros-[1,8] naphthyridines -3- formic acid；
1- cyclopropyl -6- fluorin-4-oxygens generation -7- { 4- [(3- oxos -3,4- dihydro -2H- pyridos [3,2-b] [1,4] thiazine -6- Ylmethyl)-amino]-Cyclohexylamino } -1,4- dihydros-[1,8] naphthyridines -3- formic acid；
1- cyclopropyl -6- fluorin-4-oxygens generation -7- (2- 4- [(3- oxos -3,4- dihydro -2H- pyridos [3,2-b] [1,4] thiazine - 6- ylmethyls)-amino]-piperidin-1-yl }-ethyl) -1,4- dihydros-[1,8] naphthyridines -3- formic acid；
1- cyclopropyl -6- fluorin-4-oxygens generation -7- (4- 2- [(3- oxos -3,4- dihydro -2H- pyridos [3,2-b] [1,4] thiazine - 6- ylmethyls)-amino]-ethyl }-piperazine -1- bases) -1,4- dihydros-[1,8] naphthyridines -3- formic acid；
1- cyclopropyl -6- fluorin-4-oxygens generation -7- (4- 2- [(3- oxos -3,4- dihydro -2H- pyridos [3,2-b] [1,4] thiazine - 6- ylmethyls)-amino]-ethyl }-piperidin-1-yl) -1,4- dihydros-[1,8] naphthyridines -3- formic acid；
1- cyclopropyl -6- fluorin-4-oxygens generation -7- 2- [1- (3- oxos -3,4- dihydro -2H- pyridos [3,2-b] [1,4] thiazine - 6- ylmethyls)-piperidin-4-yl]-ethylamino } -1,4- dihydros-[1,8] naphthyridines -3- formic acid；
1- cyclopropyl -6- fluorin-4-oxygens generation -7- (4- { [(3- oxos -3,4- dihydro -2H- pyridos [3,2-b] [1,4] thiazine -6- Ylmethyl)-amino]-methyl }-piperidin-1-yl) -1,4- dihydros-[1,8] naphthyridines -3- formic acid；
1- cyclopropyl -6- fluorin-4-oxygens generation -7- (4- { [(3- oxo -3,4- dihydro -2H- pyridos [3,2-b] [1,4] oxazines -6- Ylmethyl)-amino]-methyl }-Cyclohexylamino) -1,4- dihydros-[1,8] naphthyridines -3- formic acid；
1- cyclopropyl -6- fluorin-4-oxygens generation -7- (4- { [(3- oxos -3,4- dihydro -2H- pyridos [3,2-b] [1,4] thiazine -6- Ylmethyl)-amino]-methyl }-piperidin-1-yl methyl) -1,4- dihydros-[1,8] naphthyridines -3- formic acid；
1- cyclopropyl -6- fluorin-4-oxygens generation -7- { 4- [(3- oxos -3,4- dihydro -2H- pyridos [3,2-b] [1,4] thiazine -6- Ylmethyl)-amino]-piperidin-1-yl } -1,4- dihydros-[1,8] naphthyridines -3- formic acid；Or
1- cyclopropyl -6- fluorin-4-oxygens generation -7- (4- 2- [(3- oxos -3,4- dihydro -2H- pyridos [3,2-b] [1,4] thiazine - 6- ylmethyls)-amino]-ethyl }-piperazine -1- bases) -1,4- dihydro-quinoline -3- formic acid；
Or its pharmaceutically acceptable salt.
9. compound as claimed in claim 1, it is selected from：
1- cyclopropyl -6- fluorin-4-oxygens generation -7- (4- 2- [(3- oxo -3,4- dihydro -2H- pyridos [3,2-b] [1,4] oxazines - 6- ylmethyls)-amino]-ethyl }-piperazine -1- bases) -1,4- dihydros-[1,8] naphthyridines -3- formic acid；
The trans fluoro- 1- methyl -4- oxos -7- of -6- (4- { [(3- oxos -3,4- dihydro -2H- pyridos [3,2-b] [1,4] thiophenes Piperazine -6- ylmethyls)-amino]-methyl }-Cyclohexylamino) -1,4- dihydros-[1,8] naphthyridines -3- formic acid；
The trans fluoro- 1- methyl -4- oxos -7- of -6- (4- { [(3- oxo -3,4- dihydro -2H- pyridos [3,2-b] [1,4] Evil Piperazine -6- ylmethyls)-amino]-methyl }-Cyclohexylamino) -1,4- dihydros-[1,8] naphthyridines -3- formic acid；
Anti-form-1-ethyl-6- fluorin-4-oxygens generation-7- (4- { [(3- oxos-3,4- dihydro-2H- pyridos [3,2-b] [1,4] thiophenes Piperazine -6- ylmethyls)-amino]-methyl }-Cyclohexylamino) -1,4- dihydros-[1,8] naphthyridines -3- formic acid；
The fluoro- 1- methyl -4- oxos -7- of 6- (4- { 2- [(3- oxo -3,4- dihydro -2H- pyridos [3,2-b] [1,4] oxazines -6- Ylmethyl)-amino]-ethyl }-piperidin-1-yl) -1,4- dihydros-[1,8] naphthyridines -3- formic acid；Or
The fluoro- 1- methyl -4- oxos -7- of 6- (4- { 2- [(3- oxos -3,4- dihydro -2H- pyridos [3,2-b] [1,4] thiazine -6- Ylmethyl)-amino]-ethyl }-piperidin-1-yl) -1,4- dihydros-[1,8] naphthyridines -3- formic acid；
Or its pharmaceutically acceptable salt.
10. a kind of medical composition, it contains the Formulas I chemical combination as claimed in any one of claims 1-9 wherein as active ingredient Thing or its pharmaceutically acceptable salt, and at least one treatment inert excipient.
11. compound of formula I as claimed in any one of claims 1-9 wherein or its pharmaceutically acceptable salt are being prepared for pre- Purposes in anti-or treatment bacterium infection medicine.
12. purposes as claimed in claim 11, the wherein bacterium infection are selected from the group consisted of：Nosocomial pneumonia in patients, Infection in urinary tract infections, systemic infection, skin and soft tissue infection, abdomen, endocarditis, infection in diabetic foot, osteomyelitis and Central nervous system infection.
13. purposes as claimed in claim 11, the wherein bacterium infection are Lung infections.
14. purposes as claimed in claim 11, the wherein bacterium infection are surgical infections.
15. the purposes as any one of claim 11 to 14, the wherein bacterium infection are removed from office by Fermented or non-fermented Gram-negative bacteria is mediated.
16. the purposes as any one of claim 11 to 14, the wherein bacterium infection are by Acinetobacter baumannii, Bai Ke Hall moral Salmonella, citric acid bacillus, clostridium perfringen, enterobacter cloacae, Escherichia coli, the sour klebsiella of production, Cray primary Family name pneumobacillus, Serratia marcesens, germ oligotrophy unit cell or Pseudomonas aeruginosa mediation.
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Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2018528260A (en) * 2015-07-28 2018-09-27 ビオーム バイオサイエンシズ プライベート リミティド Antibacterial therapeutics and preventives
TW201833120A (en) 2017-02-17 2018-09-16 瑞士商愛杜西亞製藥有限公司 Aryloxazolidinone antibiotic compounds
WO2021009212A1 (en) 2019-07-16 2021-01-21 Idorsia Pharmaceuticals Ltd Antibacterial quinolone derivatives

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002056882A1 (en) * 2001-01-22 2002-07-25 Smithkline Beecham P.L.C. Quinolines and nitrogenated derivaive thereof substituted in 4-position by a piperidine-containing moiety and their use as antibacterial agents
WO2010045987A1 (en) * 2008-10-23 2010-04-29 Glaxo Group Limited Substituted (aza) -1-methyl-1h-quin0lin-2-0nes as antibacterials
WO2010084152A1 (en) * 2009-01-21 2010-07-29 Basilea Pharmaceutica Ag Novel bicyclic antibiotics

Family Cites Families (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5649382A (en) 1979-09-28 1981-05-02 Dainippon Pharmaceut Co Ltd 6-fluoro-7-cyclic amino-1,8-naphthylidine derivative and its salt
DE3508816A1 (en) 1985-01-10 1986-07-10 Bayer Ag, 5090 Leverkusen 6,7-DISUBSTITUTED 1-CYCLOPROPYL-1,4-DIHYDRO-4-OXO-1,8-NAPHTYRIDINE-3-CARBONIC ACIDS
CN1159809A (en) 1994-08-02 1997-09-17 普罗克特和甘保尔公司 Process for making quinolonyl lactam antimicrobials and novel intermediate compounds
JPH09323932A (en) * 1996-01-31 1997-12-16 Sankyo Co Ltd Therapeutic agent or preventive for aids
US6777420B2 (en) 2001-06-15 2004-08-17 Microbiotix, Inc. Heterocyclic antibacterial compounds
EP1401829B1 (en) 2001-06-15 2012-08-22 Microbiotix, Inc. Novel heterocyclic antibacterial compounds
TW200507841A (en) 2003-03-27 2005-03-01 Glaxo Group Ltd Antibacterial agents
BRPI0514381A (en) * 2004-07-30 2008-06-10 Palumed Sa hybrid aminoquinoline-antibiotic compounds, pharmaceutical compositions, method of preparation and use thereof
JP2008528604A (en) 2005-01-25 2008-07-31 グラクソ グループ リミテッド Antibacterial agent
NZ572381A (en) 2006-04-28 2011-01-28 Shionogi & Co Amine derivative having npy y5 receptor antagonist activity
EP2029612A1 (en) 2006-06-09 2009-03-04 Glaxo Group Limited Substituted 1-methyl-1h-quinolin-2-ones and 1-methyl-1h-1,5-naphthyridin-2-ones as antibacterials
EP2149571A4 (en) 2007-05-24 2010-09-01 Kyorin Seiyaku Kk Mutilin derivative having heterocyclic aromatic ring carboxylic acid structure in substituent at 14-position
US7884099B2 (en) 2007-11-16 2011-02-08 Cumbre Ip Ventures, L.P. Quinolone carboxylic acid-substituted rifamycin derivatives
MX2011001679A (en) 2008-08-11 2011-12-16 Biorelix Inc Flavin derivatives.
GB0815962D0 (en) 2008-09-02 2008-10-08 Merlion Pharmaceuticals Pte Ltd Hybrid antibacterial compounds and their use
TW201022279A (en) * 2008-11-14 2010-06-16 Astrazeneca Ab Chemical compounds
WO2011034971A1 (en) 2009-09-15 2011-03-24 Designmedix, Inc. Modified fluoroquinolone compounds and methods of using the same
TW201121965A (en) 2009-09-28 2011-07-01 Lg Life Sciences Ltd Use of a quinolone derivative containing 7-(4-aminomethyl-3-oxime)pyrrolidine group that is capable of inducing granulocyte colony stimulating factor for treatment of neutropenia and recovery of hematopoiesis
WO2011094260A2 (en) 2010-01-26 2011-08-04 Stc. Unm Novel bifunctional metnase/intnase inhibitors and related compositions and methods of treatment of cancer
JP5959537B2 (en) 2011-01-28 2016-08-02 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング Substituted pyridinyl-pyrimidines and their use as pharmaceuticals
DK2751083T3 (en) 2011-08-31 2018-02-26 Otsuka Pharma Co Ltd Quinolone compound
AR088691A1 (en) 2011-11-08 2014-06-25 Actelion Pharmaceuticals Ltd ANTIBIOTIC DERIVATIVES OF 2-OXO-OXAZOLIDIN-3,5-DIILO
WO2013142628A2 (en) 2012-03-20 2013-09-26 Fred Hutchinson Cancer Research Center Antibiotic compounds and compositions, and methods for identification thereof

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002056882A1 (en) * 2001-01-22 2002-07-25 Smithkline Beecham P.L.C. Quinolines and nitrogenated derivaive thereof substituted in 4-position by a piperidine-containing moiety and their use as antibacterial agents
WO2010045987A1 (en) * 2008-10-23 2010-04-29 Glaxo Group Limited Substituted (aza) -1-methyl-1h-quin0lin-2-0nes as antibacterials
WO2010084152A1 (en) * 2009-01-21 2010-07-29 Basilea Pharmaceutica Ag Novel bicyclic antibiotics
CN102361863A (en) * 2009-01-21 2012-02-22 巴斯利尔药物股份公司 Novel bicyclic antibiotics

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